U.S. patent application number 10/865414 was filed with the patent office on 2004-11-25 for method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia.
Invention is credited to Cunningham, James J., Gately, Stephen T., Gordon, Gary, Koki, Alane T., Masferrer, Jaime L., McKearn, John P..
Application Number | 20040234624 10/865414 |
Document ID | / |
Family ID | 33455837 |
Filed Date | 2004-11-25 |
United States Patent
Application |
20040234624 |
Kind Code |
A1 |
McKearn, John P. ; et
al. |
November 25, 2004 |
Method of using an integrin antagonist and one or more
antineoplastic agents as a combination therapy in the treatment of
neoplasia
Abstract
The present invention provides methods to treat or prevent
neoplasia disorders in a mammal using a combination of an integrin
antagonist and an antineoplastic agent.
Inventors: |
McKearn, John P.; (Glencoe,
MO) ; Gordon, Gary; (Highland, IL) ;
Cunningham, James J.; (Chicago, IL) ; Gately, Stephen
T.; (Palatine, IL) ; Koki, Alane T.;
(Beaufort, MO) ; Masferrer, Jaime L.; (Ballwin,
MO) |
Correspondence
Address: |
Harness Dickey
Suite 400
7700 Bonhomme
St. Louis
MO
63141
US
|
Family ID: |
33455837 |
Appl. No.: |
10/865414 |
Filed: |
June 10, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10865414 |
Jun 10, 2004 |
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09857994 |
Oct 5, 2001 |
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09857994 |
Oct 5, 2001 |
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PCT/US99/30670 |
Dec 22, 1999 |
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60113786 |
Dec 23, 1998 |
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Current U.S.
Class: |
424/649 ;
514/254.07; 514/283; 514/34; 514/492; 514/50; 514/559; 514/561;
514/651 |
Current CPC
Class: |
A61K 31/445 20130101;
A61K 31/42 20130101; A61K 41/00 20130101; A61K 31/415 20130101;
A61K 31/505 20130101; A61K 31/675 20130101; A61K 45/06 20130101;
A61K 41/0038 20130101; A61K 33/243 20190101; A61K 31/135 20130101;
A61K 31/506 20130101; A61K 31/135 20130101; A61K 2300/00 20130101;
A61K 31/415 20130101; A61K 2300/00 20130101; A61K 31/42 20130101;
A61K 2300/00 20130101; A61K 31/445 20130101; A61K 2300/00 20130101;
A61K 31/505 20130101; A61K 2300/00 20130101; A61K 31/506 20130101;
A61K 2300/00 20130101; A61K 31/675 20130101; A61K 2300/00 20130101;
A61K 33/24 20130101; A61K 2300/00 20130101; A61K 41/00 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
424/649 ;
514/034; 514/050; 514/283; 514/559; 514/561; 514/651; 514/492;
514/254.07 |
International
Class: |
A61K 031/704; A61K
031/7072; A61K 031/445; A61K 031/135 |
Claims
1-115. (cancelled).
116. A combination comprising an integrin antagonist and tamoxifen
in amounts effective, when used in a combination therapy, for
treatment of neoplasia or a neoplasia-related disorder.
117. A method for treating neoplasia or a neoplasia-related
disorder in a mammal, the method comprising administering to the
mammal a therapeutically effective amount of a combination
comprising an integrin antagonist and tamoxifen.
118. The method of claim 117 wherein the neoplasia or
neoplasia-related disorder is breast cancer.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to combinations and methods
for treatment or prevention of neoplasia disorders in a mammal
using two or more components with at least one component being an
antiangiogenesis agent.
BACKGROUND OF THE INVENTION
[0002] A neoplasm, or tumor, is an abnormal, unregulated, and
disorganized proliferation of cell growth. A neoplasm is malignant,
or cancerous, if it has properties of destructive growth,
invasiveness and metastasis. Invasiveness refers to the local
spread of a neoplasm by infiltration or destruction of surrounding
tissue, typically breaking through the basal laminas that define
the boundaries of the tissues, thereby often entering the body's
circulatory system. Metastasis typically refers to the
dissemination of tumor cells by lymphotics or blood vessels.
Metastasis also refers to the migration of tumor cells by direct
extension through serous cavities, or subarachnoid or other spaces.
Through the process of metastasis, tumor cell migration to other
areas of the body establishes neoplasms in areas away from the site
of initial appearance.
[0003] Cancer is now the second leading cause of death in the
United States and over 8,000,000 persons in the United States have
been diagnosed with cancer. In 1995, cancer accounted for 23.3% of
all deaths in the United States. (See U.S. Dept. of Health and
Human Services, National Center for Health Statistics, Health
United States 1996-97 and Injury Chartbook 117 (1997)).
[0004] Cancer is not fully understood on the molecular level. It is
known that exposure of a cell to a carcinogen such as certain
viruses, certain chemicals, or radiation, leads to DNA alteration
that inactivates a "suppressive" gene or activates an "oncogene".
Suppressive genes are growth regulatory genes, which upon mutation,
can no longer control cell growth. Oncogenes are initially normal
genes (called prooncogenes) that by mutation or altered context of
expression become transforming genes. The products of transforming
genes cause inappropriate cell growth. More than twenty different
normal cellular genes can become oncogenes by genetic alteration.
Transformed cells differ from normal cells in many ways, including
cell morphology, cell-to-cell interactions, membrane content,
cytoskeletal structure, protein secretion, gene expression and
mortality (transformed cells can grow indefinitely).
[0005] Cancer is now primarily treated with one or a combination of
three types of therapies: surgery, radiation, and chemotherapy.
Surgery involves the bulk removal of diseased tissue. While surgery
is sometimes effective in removing tumors located at certain sites,
for example, in the breast, colon, and skin, it cannot be used in
the treatment of tumors located in other areas, such as the
backbone, nor in the treatment of disseminated neoplastic
conditions such as leukemia.
[0006] Chemotherapy involves the disruption of cell replication or
cell metabolism. It is used most often in the treatment of breast,
lung, and testicular cancer.
[0007] The adverse effects of systemic chemotherapy used in the
treatment of neoplastic disease is most feared by patients
undergoing treatment for cancer. Of these adverse effects nausea
and vomiting are the most common and severe side effects. Other
adverse side effects include cytopenia, infection, cachexia,
mucositis in patients receiving high doses of chemotherapy with
bone marrow rescue or radiation therapy; alopecia (hair loss);
cutaneous complications (see M. D. Abeloff, et al: Alopecia and
Cutaneous Complications. P. 755-56. In Abeloff, M. D., Armitage, J.
O., Lichter, A. S., and Niederhuber, J. E. (eds) Clinical Oncology.
Churchill Livingston, N.Y., 1992, for cutaneous reactions to
chemotherapy agents), such as pruritis, urticaria, and angioedema;
neurological complications; pulmonary and cardiac complications in
patients receiving radiation or chemotherapy; and reproductive and
endocrine complications.
[0008] Chemotherapy-induced side effects significantly impact the
quality of life of the patient and may dramatically influence
patient compliance with treatment.
[0009] Additionally, adverse side effects associated with
chemotherapeutic agents are generally the major dose-limiting
toxicity (DLT) in the administration of these drugs. For example,
mucositis, is one of the major dose limiting toxicity for several
anticancer agents, including the antimetabolite cytotoxic agents
5-FU, methotrexate, and antitumor antibiotics, such as doxorubicin.
Many of these chemotherapy-induced side effects if severe, may lead
to hospitalization, or require treatment with analgesics for the
treatment of pain.
[0010] The adverse side effects induced by chemotherapeutic agents
and radiation therapy have become of major importance to the
clinical management of cancer patients.
[0011] U.S. Pat. No. 5,854,205 describes an isolated endostatin
protein that is an inhibitor of endothelial cell proliferation and
angiogenesis. U.S. Pat. No. 5,843,925 describes a method for
inhibiting angiogenesis and endothelial cell proliferation using a
7-[substituted amino]-9-[(substituted
glycy10amido]-6-demethyl-6-deoxytetracycline. U.S. Pat. No.
5,863,538 describes methods and compositions for targeting tumor
vasculature of solid tumors using immunological and growth
factor-based reagents in combination with chemotherapy and
radiation. U.S. Pat. No. 5,837,682 describes the use of fragments
of an endothelial cell proliferation inhibitor, angiostatin. U.S.
Pat. No. 5,861,372 describes the use of an aggregate endothelial
inhibitor, angiostatin, and it use in inhibiting angiogenesis. U.S.
Pat. No. 5,885,795 describes methods and compositions for treating
diseases mediated by undesired and uncontrolled angiogenesis by
administering purified angiostatin or angiostatin derivatives.
[0012] PCT/GB97/00650 describes the use of cinnoline derivatives
for use in the production of an antiangiogenic and/or vascular
permeability reducing effect.
[0013] PCT/US97/09610 describes administration of an anti-endogin
monoclonal antibody, or fragments thereof, which is conjugated to
at least one angiogenesis inhibitor or antitumor agent for use in
treating tumor and angiogenesis-associated diseases.
[0014] PCT/IL96/00012 describes a fragment of the Thrombin B-chain
for the treatment of cancer.
[0015] PCT/US95/16855 describes compositions and methods of killing
selected tumor cells using recombinant viral vectors.
[0016] Ravaud, A. et al. describes the efficacy and tolerance of
interleukin-2 (IL-2), interferon alpha-2a, and fluorouracil in
patients with metastatic renal cell carcinoma. J. Clin. Oncol. 16,
No. 8, 2728-32, 1998. Stadler, W. M. et al. describes the response
rate and toxicity of oral 13-cis-retinoic acid added to an
outpatient regimen of subcutaneous interleukin-2 and interferon
alpha in patients with metastatic renal cell carcinoma. J. Clin.
Oncol. 16, No. 5, 1820-25, 1998. Rosenbeg, S. A. et al. describes
treatment of patients with metastatic melanoma using chemotherapy
with cisplatin, dacarbazine, and tamoxifen alone or in combination
with interleukin-2 and interferon alpha-2b. J. Clin. Oncol. 17, No.
3, 968-75, 1999. Tourani, J-M. et al describes treatment of renal
cell carcinoma using interleukin-2, and interferon alpha-2a
administered in combination with fluorouracil. J. Clin. Oncol. 16,
No. 7, 2505-13, 1998. Majewski, S. describes the anticancer action
of retinoids, vitamin D3 and cytokines (interferons and
interleukin-12) as related to the antiangiogenic and
antiproliferative effects. J. Invest. Dermatol. 108, No. 4, 571,
1997. Ryan, C. W. describes treatment of patients with metastatic
renal cell cancer with GM-CSF, Interleukin-2, and interferon-alpha
plus oral cis-retinoic acid in patients with metastatic renal cell
cancer. J. Invest. Med. 46, No. 7, 274A, 1998. Tai-Ping, D.
describes potential anti-angiogenic therapies. Trends Pharmacol.
Sci. 16, No. 2, 57-66, 1995. Brembeck, F. H. describes the use of
13-cis retinoic acid and interferon alpha to treat UICC stage
III/IV pancreatic cancer. Gastroenterology 114, No. 4, Pt. 2, A569,
1998. Brembeck, F. H. describes the use of 13-cis retinoic acid and
interferon alpha in patients with advanced pancreatic carcinoma.
Cancer 83, No. 11, 2317-23, 1998. Mackean, M. J. describes the use
of roquinimex (Linomide) and alpha interferon in patients with
advanced malignant melanoma or renal carcinoma. Br. J. Cancer 78,
No. 12, 1620-23, 1998 Jayson, G. C. describes the use of
interleukin 2 and interleukin-interferon alpha in advanced renal
cancer. Br. J. Cancer 78, No. 3, 366-69, 1998. Abraham, J. M.
describes the use of Interleukin-2, interferon alpha and
5-fluorouracil in patients with metastatic renal carcinoma. Br. J.
Cancer 78, Suppl. 2, 8, 1998. Soori, G. S. describes the use of
chemo-biotherapy with chlorambucil and alpha interferon in patients
with non-hodgkins lymphoma. Blood 92, No. 10, Pt. 2 Suppl. 1, 240b,
1998. Enschede, S. H. describes the use of interferon alpha added
to an anthracycline-based regimen in treating low grade and
intermediate grade non-hodgkin's lymphoma. Blood 92, No. 10, Pt. 1
Suppl. 1, 412a, 1998. Schachter, J. describes the use of a
sequential multi-drug chemotherapy and biotherapy with interferon
alpha, a four drug chemotherapy regimen and GM-CSF. Cancer Biother.
Radiopharm. 13, No. 3, 155-64, 1998. Mross, K. describes the use of
retinoic acid, interferon alpha and tamoxifen in metastatic breast
cancer patients. J. Cancer Res. Clin. Oncology. 124 Suppl. 1 R123,
1998. Muller, H. describes the use of suramin and tamoxifen in the
treatment of advanced and metastatic pancreatic carcinoma. Eur. J.
Cancer 33, Suppl. 8, S50, 1997. Rodriguez, M. R. describes the use
of taxol and cisplatin, and taxotere and vinorelbine in the
treatment of metastatic breast cancer. Eur. J. Cancer 34, Suppl. 4,
S17-S18, 1998. Formenti, C. describes concurrent paclitaxel and
radiation therapy in locally advanced breast cancer patients. Eur.
J. Cancer 34, Suppl. 5, S39, 1998. Durando, A. describes
combination chemotherapy with paclitaxel (T) and epirubicin (E) for
metastatic breast cancer. Eur. J. Cancer 34, Suppl. 5, S41, 1998.
Osaki, A. describes the use of a combination therapy with
mitomycin-C, etoposide, doxifluridine and medroxyprogesterone
acetate as second-line therapy for advanced breast cancer. Eur. J.
Cancer 34, Suppl. 5, S59, 1998. Lode, H. et al. describes Synergy
between an antiangiogenic integrin alpha v antagonist and an
antibody-cytokine fusion protein eradicates spontaneous tumor
metastasis. Proc. Nat. Acad. Sci. USA., 96 (4), 1591-1596, 1999.
Giannis, A. et al describes Integrin antagonists and other low
molecular weight compounds as inhibitors of angiogenesis: new drugs
in cancer therapy. Angew. Chem. Int. Ed. Engl. 36(6), 588-590,
1997. Takada, Y. et al describes the structures and functions of
integrins. Jikken Igaku 14 (17), 2317-2322, 1996. Varner, J. et al.
Tumor angiogenesis and the role of vascular cell integrin
alphavbeta3. Impt. Adv. Onc., 69-87 Ref:259. 1996.
[0017] WO 98/16,227 describes a method of using
[Pyrozol-1-yl]benzenesulfo- namides in the treatment of and
prevention of neoplasia. WO 98/22,101 describes a method of using
[Pyrozol-1-yl]benzenesulfonamides as anti-angiogenic agents.
DESCRIPTION OF THE INVENTION
[0018] Treatment or prevention of a neoplasia disorder in a
mammalin need of such treatment or prevention is provided by
methods and combinations using two or more components with at least
one component being an integrin antagonist.
[0019] The method comprises treating a mammal with a
therapeutically effective amount of a combination comprising two or
more agents. The first agent is a integrin antagonist. The second
agent or agents is an antineoplastic agent. Besides being useful
for human treatment, the present invention is also useful for
veterinary treatment of companion animals, exotic animals and farm
animals, including mammals, rodents, and the like. More preferred
animals include horses, dogs, and cats.
[0020] The methods and combinations of the present invention may be
used for the treatment or prevention of neoplasia disorders
including the group consisting of acral lentiginous melanoma,
actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma,
adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors,
bartholin gland carcinoma, basal cell carcinoma, bronchial gland
carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma,
cavernous, cholangiocarcinoma, chondosarcoma, choriod plexus
papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal
sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma,
endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's
sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ
cell tumors, glioblastoma, glucagonoma, hemangiblastomas,
hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic
adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial
neoplasia, interepithelial squamous cell neoplasia, invasive
squamous cell carcinoma, large cell carcinoma, leiomyosarcoma,
lentigo maligna melanomas, malignant melanoma, malignant
mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma,
meningeal, mesothelial, metastatic carcinoma, mucoepidermoid
carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular
melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma,
pancreatic polypeptide, papillary serous adenocarcinoma, pineal
cell, pituitary tumors, plasmacytoma, pseudosarcoma, pulmonary
blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,
sarcoma, serous carcinoma, small cell carcinoma, soft tissue
carcinomas, somatostatin-secreting tumor, squamous carcinoma,
squamous cell carcinoma, submesothelial, superficial spreading
melanoma, undifferentiated carcinoma, uveal melanoma, verrucous
carcinoma, vipoma, well differentiated carcinoma, and Wilm's
tumor.
[0021] The methods and combinations of the present invention
provide one or more benefits. Combinations of integrin antagonists
with the compounds, compositions, agents and therapies of the
present invention are useful in treating and preventing neoplasia
disorders. Preferably, the integrin antagonist and the compounds,
compositions, agents and therapies of the present invention are
administered in combination at a low dose, that is, at a dose lower
than has been conventionally used in clinical situations.
[0022] A benefit of lowering the dose of the compounds,
compositions, agents and therapies of the present invention
administered to a mammal includes a decrease in the incidence of
adverse effects associated with higher dosages. For example, by the
lowering the dosage of a chemotherapeutic agent such as
methotrexate, a reduction in the frequency and the severity of
nausea and vomiting will result when compared to that observed at
higher dosages. Similar benefits are contemplated for the
compounds, compositions, agents and therapies in combination with
the integrin antagonists of the present invention.
[0023] By lowering the incidence of adverse effects, an improvement
in the quality of life of a patient undergoing treatment for cancer
is contemplated. Further benefits of lowering the incidence of
adverse effects include an improvement in patient compliance, a
reduction in the number of hospitalizations needed for the
treatment of adverse effects, and a reduction in the administration
of analgesic agents needed to treat pain associated with the
adverse effects.
[0024] Alternatively, the methods and combination of the present
invention can also maximize the therapeutic effect at higher
doses.
[0025] When administered as a combination, the therapeutic agents
can be formulated as separate compositions which are given at the
same time or different times, or the therapeutic agents can be
given as a single composition.
[0026] When used as a therapeutic the compounds described herein
are preferably administered with a physiologically acceptable
carrier. A physiologically acceptable carrier is a formulation to
which the compound can be added to dissolve it or otherwise
facilitate its administration. Examples of physiologically
acceptable carriers include, but are not limited to, water, saline,
physiologically buffered saline. Additional examples are provided
below.
[0027] The term "pharmaceutically acceptable" is used adjectivally
herein to mean that the modified noun is appropriate for use in a
pharmaceutical product. Pharmaceutically acceptable cations include
metallic ions and organic ions. More preferred metallic ions
include, but are not limited to appropriate alkali metal salts,
alkaline earth metal salts and other physiological acceptable metal
ions. Exemplary ions include aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc in their usual valences. Preferred
organic ions include protonated tertiary amines and quaternary
ammonium cations, including in part, trimethylamine, diethylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and
procaine. Exemplary pharmaceutically acceptable acids include
without limitation hydrochloric acid, hydrobromic acid, phosphoric
acid, sulfuric acid, methanesulfonic acid, acetic acid, formic
acid, tartaric acid, maleic acid, malic acid, citric acid,
isocitric acid, succinic acid, lactic acid, gluconic acid,
glucuronic acid, pyruvic acid oxalacetic acid, fumaric acid,
propionic acid, aspartic acid, glutamic acid, benzoic acid, and the
like.
[0028] A compound of the present invention can be formulated as a
pharmaceutical composition. Such a composition can then be
administered orally, parenterally, by inhalation spray, rectally,
or topically in dosage unit formulations containing conventional
nontoxic pharmaceutically acceptable carriers, adjuvants, and
vehicles as desired. Topical administration can also involve the
use of transdermal administration such as transdermal patches or
iontophoresis devices. The term parenteral as used herein includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection, or infusion techniques. Formulation of drugs is
discussed in, for example, Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.; 1975.
Another example of includes Liberman, H. A. and Lachman, L., Eds.,
Pharmaceutical Dosaae Forms, Marcel Decker, New York, N.Y.,
1980.
[0029] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can also be a
sterile injectable solution or suspension in a nontoxic
parenterally acceptable dilutent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables. Dimethyl
acetamide, surfactants including ionic and non-ionic detergents,
polyethylene glycols can be used. Mixtures of solvents and wetting
agents such as those discussed above are also useful.
[0030] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable nonirritating excipient
such as cocoa butter, synthetic mono- di- or triglycerides, fatty
acids and polyethylene glycols that are sold at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0031] Solid dosage forms for oral administration can include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the compounds of this invention are ordinarily
combined with one or more adjuvants appropriate to the indicated
route of administration. If administered per os, a contemplated
aromatic sulfone hydroximate inhibitor compound can be admixed with
lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric
and sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted
or encapsulated for convenient administration. Such capsules or
tablets can contain a controlled-release formulation as can be
provided in a dispersion of active compound in hydroxypropylmethyl
cellulose. In the case of capsules, tablets, and pills, the dosage
forms can also comprise buffering agents such as sodium citrate,
magnesium or calcium carbonate or bicarbonate. Tablets and pills
can additionally be prepared with enteric coatings.
[0032] For therapeutic purposes, formulations for parenteral
administration can be in the form of aqueous or non-aqueous
isotonic sterile injection solutions or suspensions. These
solutions and suspensions can be prepared from sterile powders or
granules having one or more of the carriers or diluents mentioned
for use in the formulations for oral administration. A contemplated
aromatic sulfone hydroximate inhibitor compound can be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, and/or various buffers. Other adjuvants and modes of
administration are well and widely known in the pharmaceutical
art.
[0033] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions can also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavoring, and perfuming agents.
[0034] The amount of active ingredient that can be combined with
the carrier materials to produce a single dosage form varies
depending upon the mammalian host treated and the particular mode
of administration.
[0035] The present invention further includes kits comprising and
integrin antagonist and an antineoplastic agent.
[0036] The term "treatment" refers to any process, action,
application, therapy, or the like, wherein a mammal, including a
human being, is subject to medical aid with the object of improving
the mammal's condition, directly or indirectly.
[0037] The term "inhibition," in the context of neoplasia, tumor
growth or tumor cell growth, may be assessed by delayed appearance
of primary or secondary tumors, slowed development of primary or
secondary tumors, decreased occurrence of primary or secondary
tumors, slowed or decreased severity of secondary effects of
disease, arrested tumor growth and regression of tumors, among
others. In the extreme, complete inhibition, is referred to herein
as prevention or chemoprevention.
[0038] The term "prevention" includes either preventing the onset
of clinically evident neoplasia altogether or preventing the onset
of a preclinically evident stage of neoplasia in individuals at
risk. Also intended to be encompassed by this definition is the
prevention of initiation for malignant cells or to arrest or
reverse the progression of premalignant cells to malignant cells.
This includes prophylactic treatment of those at risk of developing
the neoplasia.
[0039] The term "angiogenesis" refers to the process by which tumor
cells trigger abnormal blood vessel growth to create their own
blood supply, and is a major target of cancer research.
Angiogenesis is believed to be the mechanism via which tumors get
needed nutrients to grow and metastasize to other locations in the
body. Antiangiogenic agents interfere with these processes and
destroy or control tumors.
[0040] Angiogenesis is an attractive therapeutic target because it
is a multi-step process that occurs in a specific sequence, thus
providing several possible targets for drug action. Examples of
agents that interfere with several of these steps include
thrombospondin-1, angiostatin, endostatin, interferon alpha and
compounds such as matrix metalloproteinase (MMP) inhibitors that
block the actions of enzymes that clear and create paths for newly
forming blood vessels to follow; compounds, such as
.alpha..sub.v.beta..sub.3 inhibitors, that interfere with molecules
that blood vessel cells use to bridge between a parent blood vessel
and a tumor; agents, such as specific COX-2 inhibitors, that
prevent the growth of cells that form new blood vessels; and
protein-based compounds that simultaneously interfere with several
of these targets.
[0041] Antiangiogenic therapy may offer several advantages over
conventional chemotherapy for the treatment of cancer.
[0042] Antiangiogenic agents have low toxicity in preclinical
trials and development of drug resistance has not been observed
(Folkman, J., Seminars in Medicine of the Beth Israel Hospital,
Boston 333(26): 1757-1763, 1995). As angiogenesis is a complex
process, made up of many steps including invasion, proliferation
and migration of endothelial cells, it can be anticipated that
combination therapies will be most effective. Kumar and Armstrong
describe anti-angiogenesis therapy used as an adjunct to
chemotherapy, radiation therapy, or surgery. (Kumar, CC, and
Armstrong, L., Tumor-induced angiogenesis: a novel target for drug
therapy?, Emerging Drugs (1997), 2, 175-190).
[0043] The phrase "therapeutically-effective, is intended to
qualify the amount of each agent that will achieve the goal of
improvement in neoplastic disease severity and the frequency of
neoplastic disease over treatment of each agent by itself, while
avoiding adverse side effects typically associated with alternative
therapies.
[0044] A "therapeutic effect" or "therapeutic effective amount" is
intended to qualify the amount of an anticancer agent required to
relieve to some extent one or more of the symptoms of a neoplasia
disorder, including, but is not limited to: 1) reduction in the
number of cancer cells; 2) reduction in tumor size; 3) inhibition
(i.e., slowing to some extent, preferably stopping) of cancer cell
infiltration into peripheral organs; 3) inhibition (i.e., slowing
to some extent, preferably stopping) of tumor metastasis; 4)
inhibition, to some extent, of tumor growth; 5) relieving or
reducing to some extent one or more of the symptoms associated with
the disorder; and/or 6) relieving or reducing the side effects
associated with the administration of anticancer agents.
[0045] The phrase "combination therapy" (or "co-therapy") embraces
the administration of an integrin antagonist and an antineoplastic
agent as part of a specific treatment regimen intended to provide a
beneficial effect from the co-action of these therapeutic agents.
The beneficial effect of the combination includes, but is not
limited to, pharmacokinetic or pharmacodynamic co-action resulting
from the combination of therapeutic agents. Administration of these
therapeutic agents in combination typically is carried out over a
defined time period (usually minutes, hours, days or weeks
depending upon the combination selected). "Combination therapy"
generally is not intended to encompass the administration of two or
more of these therapeutic agents as part of separate monotherapy
regimens that incidentally and arbitrarily result in the
combinations of the present invention. "Combination therapy" is
intended to embrace administration of these therapeutic agents in a
sequential manner, that is, wherein each therapeutic agent is
administered at a different time, as well as administration of
these therapeutic agents, or at least two of the therapeutic
agents, in a substantially simultaneous manner. Substantially
simultaneous administration can be accomplished, for example, by
administering to the subject a single capsule having a fixed ratio
of each therapeutic agent or in multiple, single capsules for each
of the therapeutic agents. Sequential or substantially simultaneous
administration of each therapeutic agent can be effected by any
appropriate route including, but not limited to, oral routes,
intravenous routes, intramuscular routes, and direct absorption
through mucous membrane tissues. The therapeutic agents can be
administered by the same route or by different routes. For example,
a first therapeutic agent of the combination selected may be
administered by intravenous injection while the other therapeutic
agents of the combination may be administered orally.
Alternatively, for example, all therapeutic agents may be
administered orally or all therapeutic agents may be administered
by intravenous injection. The sequence in which the therapeutic
agents are administered is not narrowly critical. "Combination
therapy" also can embrace the administration of the therapeutic
agents as described above in further combination with other
biologically active ingredients (such as, but not limited to, a
second and different antineoplastic agent) and non-drug therapies
(such as, but not limited to, surgery or radiation treatment).
Where the combination therapy further comprises radiation
treatment, the radiation treatment may be conducted at any suitable
time so long as a beneficial effect from the co-action of the
combination of the therapeutic agents and radiation treatment is
achieved. For example, in appropriate cases, the beneficial effect
is still achieved when the radiation treatment is temporally
removed from the administration of the therapeutic agents, perhaps
by days or even weeks.
[0046] The phrases "low dose" or "low dose amount", in
characterizing a therapeutically effective amount of the
antiangiogenesis agent and the antineoplastic agent or therapy in
the combination therapy, defines a quantity of such agent, or a
range of quantity of such agent, that is capable of improving the
neoplastic disease severity while reducing or avoiding one or more
antineoplastic-agent-induced side effects, such as myelosupression,
cardiac toxicity, alopecia, nausea or vomiting.
[0047] The phrase "adjunctive therapy" encompasses treatment of a
subject with agents that reduce or avoid side effects associated
with the combination therapy of the present invention, including,
but not limited to, those agents, for example, that reduce the
toxic effect of anticancer drugs, e.g., bone resorption inhibitors,
cardioprotective agents; prevent or reduce the incidence of nausea
and vomiting associated with chemotherapy, radiotherapy or
operation; or reduce the incidence of infection associated with the
administration of myelosuppressive anticancer drugs.
[0048] The phrase an "immunotherapeutic agent" refers to agents
used to transfer the immunity of an immune donor, e.g., another
person or an animal, to a host by inoculation. The term embraces
the use of serum or gamma gobulin containing performed antibodies
produced by another individual or an animal; nonspecific systemic
stimulation; adjuvants; active specific immunotherapy; and adoptive
immunotherapy. Adoptive immunotherapy refers to the treatment of a
disease by therapy or agents that include host inoculation of
sensitized lymphocytes, transfer factor, immune RNA, or antibodies
in serum or gamma globulin.
[0049] The phrase a device" refers to any appliance, usually
mechanical or electrical, designed to perform a particular
function.
[0050] The phrase a "vaccine" includes agents that induce the
patient's immune system to mount an immune response against the
tumor by attacking cells that express tumor associated antigens
(TAAs).
[0051] The phrase "multi-functional proteins encompass a variety of
pro-angiogenic factors that include basic and acid fibroblast
growth factors (bFGF and aFGF) and vascular permeability
factor/vascular endothelial growth factor (VPF/VEGF) (Bikfalvi, A.
et al., Endocrine Reviews 18: 26-45, 1997). Several endogenous
antiangiogenic factors have also been characterized as
multi-functional proteins and include angiostatin (O'Reilly et al.,
Cell (Cambridge, Mass) 79(2): 315-328, 1994), endostatin (O'Reilly
et al, Cell (Cambridge, Mass) 88(2): 277-285, 1997), interferon
alpha. (Ezekowitz et al, N. Engl. J. Med., May 28, 326(22)
1456-1463, 1992), thrombospondin (Good et al, Proc Natl Acad Sci
USA 87(17): 6624-6628, 1990; Tolsma et al, J Cell Biol 122(2):
497-511, 1993), and platelet factor 4 (PF4) (Maione et al, Science
247:(4938): 77-79, 1990).
[0052] The phrase an "analgesic agent" refers to an agent that
relieves pain without producing anesthesia or loss of consciousness
generally by altering the perception of nociceptive stimuli.
[0053] The phrase a "radiotherapeutic agent" refers to the use of
electromagnetic or particulate radiation in the treatment of
neoplasia.
[0054] The term "pBATT" embraces" or "Protein-Based Anti-Tumor
Therapies," refers to protein-based therapeutics for solid tumors.
The pBATTs include proteins that have demonstrated efficacy against
tumors in animal models or in humans. The protein is then modified
to increase its efficacy and toxicity profile by enhancing its
bioavailability and targeting.
[0055] "Angiostatin" is a 38 kD protein comprising the first three
or four kringle domains of plasminogen and was first described in
1994 (O'Reilly, M. S. et al., Cell (Cambridge, Mass.) 79(2):
315-328, 1994). Mice bearing primary (Lewis lung carcinoma-low
metastatic) tumors did not respond to angiogenic stimuli such as
bFGF in a corneal micropocket assay and the growth of metastatic
tumors in these mice was suppressed until the primary tumor was
excised. The factor responsible for the inhibition of angiogenesis
and tumor growth was designated mouse angiostatin. Angiostatin was
also shown to inhibit the growth of endothelial cells in vitro.
[0056] Human angiostatin can be prepared by digestion of
plasminogen by porcine elastase (O'Reilly, et al., Cell 79(2):
315-328, 1994) or with human metalloelastase (Dong et al., Cell 88,
801-810, 1997). The angiostatin produced via porcine elastase
digestion inhibited the growth of metastases and primary tumors in
mice. O'Reilly et al., (Cell 79(2): 315-328, 1994) demonstrated
that human angiostatin inhibited metastasis of Lewis lung carcinoma
in SCID mice. The same group (O'Reilly, M. S. et al., Nat. Med.
(N.Y.) 2(6): 689-692, 1996) subsequently showed that human
angiostatin inhibited the growth of the human tumors PC3 prostate
carcinoma, clone A colon carcinoma, and MDA-MB breast carcinoma in
SCID mice. Human angiostatin also inhibited the growth of the mouse
tumors Lewis lung carcinoma, T241 fibrosarcoma and M5076 reticulum
cell carcinoma in C57B1 mice. Because these enzymatically-prepared
angiostatins are not well characterized biochemically, the precise
composition of the molecules is not known.
[0057] Angiostatins of known composition can be prepared by means
of recombinant DNA technology and expression in heterologous cell
systems. Recombinant human angiostatin comprising Kringle domains
one through four (K1-4) has been produced in the yeast Pichia
pastoris (Sim et al., Cancer Res 57: 1329-1334, 1997). The
recombinant human protein inhibited growth of endothelial cells in
vitro and inhibited metastasis of Lewis lung carcinoma in C57B1
mice. Recombinant murine angiostatin (K1-4) has been produced in
insect cells (Wu et al., Biochem Biophys Res Comm 236: 651-654,
1997). The recombinant mouse protein inhibited endothelial cell
growth in vitro and growth of primary Lewis lung carcinoma in vivo.
These experiments demonstrated that the first four kringle domains
are sufficient for angiostatin activity but did not determine which
kringle domains are necessary.
[0058] Cao et al. (J. Biol. Chem. 271: 29461-29467, 1996), produced
fragments of human plasminogen by proteolysis and by expression of
recombinant proteins in E. coli. These authors showed that kringle
one and to a lesser extent kringle four of plasminogen were
responsible for the inhibition of endothelial cell growth in vitro.
Specifically, kringles 1-4 and 1-3 inhibited at similar
concentrations, while K1 alone inhibited endothelial cell growth at
four-fold higher concentrations. Kringles two and three inhibited
to a lesser extent. More recently Cao et al. (J Biol Chem 272:
22924-22928, 1997), showed that recombinant mouse or human kringle
five inhibited endothelial cell growth at lower concentrations than
angiostatin (K1-4). These experiments demonstrated in vitro
angiostatin-like activity but did not address in vivo action
against tumors and their metastases.
[0059] PCT publication WO 95/29242 discloses purification of a
protein from blood and urine by HPLC that inhibits proliferation of
endothelial cells. The protein has a molecular weight between 38
kilodaltons and 45 kilodaltons and an amino acid sequence
substantially similar to that of a murine plasminogen fragment
beginning at amino acid number 79 of a murine plasminogen molecule.
PCT publication WO 96/41194, discloses compounds and methods for
the diagnosis and monitoring of angiogenesis-dependent diseases.
PCT publication WO 96/35774 discloses the structure of protein
fragments, generally corresponding to kringle structures occurring
within angiostatin. It also discloses aggregate forms of
angiostatin, which have endothelial cell inhibiting activity, and
provides a means for inhibiting angiogenesis of tumors and for
treating angiogenic-mediated diseases.
[0060] "Endostatin" is a 20-kDa (184 amino acid) carboxy fragment
of collagen XVIII, is an angiogenesis inhibitor produced by a
hemangioendothelioma (O'Reilly, M. S. et al., Cell (Cambridge,
Mass.) 88(2): 277-285, 1997); and WO 97/15666). Endostatin
specifically inhibits endothelial proliferation and inhibits
angiogenesis and tumor growth. Primary tumors treated with
non-refolded suspensions of E. coli-derived endostatin regressed to
dormant microscopic lesions. Toxicity was not observed and
immunohistochemical studies revealed a blockage of angiogenesis
accompanied by high proliferation balanced by apoptosis in tumor
cells.
[0061] "Interferon .alpha." (IFN.alpha.) is a family of highly
homologous, species-specific proteins that possess complex
antiviral, antineoplastic and immunomodulating activities
(Extensively reviewed in the monograph "Antineoplastic agents,
interferon alfa", American Society of Hospital Pharmacists, Inc.,
1996). Interferon alpha. also has anti-proliferative, and
antiangiogenic properties, and has specific effects on cellular
differentiation (Sreevalsan, in "Biologic Therapy of Cancer", pp.
347-364, (eds. V. T. DeVita Jr., S. Hellman, and S. A. Rosenberg),
J. B. Lippincott Co, Philadelphia, Pa., 1995).
[0062] Interferon .alpha. is effective against a variety of cancers
including hairy cell leukemia, chronic myelogenous leukemia,
malignant melanoma, and Kaposi's sarcoma. The precise mechanism by
which IFN.alpha. exerts its anti-tumor activity is not entirely
clear, and may differ based on the tumor type or stage of disease.
The anti-proliferative properties of IFN.alpha., which may result
from the modulation of the expression of oncogenes and/or
proto-oncogenes, have been demonstrated on both tumor cell lines
and human tumors growing in nude mice (Gutterman, J. U., Proc.
Natl. Acad. Sci., USA 91: 1198-1205, 1994).
[0063] Interferon is also considered an anti-angiogenic factor, as
demonstrated through the successful treatment of hemangiomas in
infants (Ezekowitz et al, N. Engl. J. Med., May 28, 326(22)
1456-1463, 1992) and the effectiveness of IFN.alpha. against
Kaposi's sarcoma (Krown, Semin Oncol 14(2 Suppl 3): 27-33, 1987).
The mechanism underlying these anti-angiogenic effects is not
clear, and may be the result of IFN.alpha. action on the tumor
(decreasing the secretion of pro-angiogenic factors) or on the
neo-vasculature. IFN receptors have been identified on a variety of
cell types (Navarro et al., Modern Pathology 9(2): 150-156,
1996).
[0064] U.S. Pat. No. 4,530,901, by Weissmann, describes the cloning
and expression of IFN-.alpha.-type molecules in transformed host
strains. U.S. Pat. No. 4,503,035, Pestka, describes an improved
processes for purifying 10 species of human leukocyte interferon
using preparative high performance liquid chromatography. U.S. Pat.
No. 5,231,176, Goeddel, describes the cloning of a novel distinct
family of human leukocyte interferons containing in their mature
form greater than 166 and no more than 172 amino acids.
[0065] U.S. Pat. No. 5,541,293, by Stabinsky, describes the
synthesis, cloning, and expression of consensus human interferons.
These are non-naturally occurring analogues of human (leukocyte)
interferon-.alpha. assembled from synthetic oligonucleotides. The
sequence of the consensus interferon was determined by comparing
the sequences of 13 members of the IFN-.alpha. family of
interferons and selecting the preferred amino acid at each
position. These variants differ from naturally occurring forms in
terms of the identity and/or location of one or more amino acids,
and one or more biological and pharmacological properties (e.g.,
antibody reactivity, potency, or duration effect) but retain other
such properties.
[0066] "Thrombospondin-1" (TSP-1) is a trimer containing three
copies of a 180 kDa polypeptide. TSP-1 is produced by many cell
types including platelets, fibroblasts, and endothelial cells (see
Frazier, Curr Opin Cell Biol 3(5): 792-799, 1991) and the cDNA
encoding the subunit has been cloned (Hennessy, et al., 1989, J
Cell Biol 108(2): 729-736; Lawler and Hynes, J Cell Biol 103(5):
1635-1648, 1986). Native TSP-1 has been shown to block endothelial
cell migration in vitro and neovascularization in vivo (Good et al,
Proc Natl Acad Sci USA 87(17): 6624-6628, 1990). Expression of
TSP-1 in tumor cells also suppresses tumorigenesis and
tumor-induced angiogenesis (Sheibani and Frazier, Proc Natl Acad
Sci USA 92(15) 6788-6792, 1995; Weinstat-Saslow et al., Cancer Res
54(24):6504-6511, 1994). The antiangiogenic activity of TSP-1 has
been shown to reside in two distinct domains of this protein
(Tolsma et al, J Cell Biol 122(2): 497-511, 1993). One of these
domains consists of residues 303 to 309 of native TSP-1 and the
other consists of residues 481 to 499 of TSP-1. Another important
domain consists of the sequence CSVTCG which appears to mediate the
binding of TSP-1 to some tumor cell types (Tuszynski and Nicosia,
Bioessays 18(1): 71-76, 1996). These results suggest that CSVTCG,
or related sequences, can be used to target other moieties to tumor
cells. Taken together, the available data indicate that TSP-1 plays
a role in the growth and vascularization of tumors. Subfragments of
TSP-1, then, may be useful as antiangiogenic components of chimeras
and/or in targeting other proteins to specific tumor cells.
Subfragments may be generated by standard procedures (such as
proteolytic fragmentation, or by DNA amplification, cloning,
expression, and purification of specific TSP-1 domains or
subdomains) and tested for antiangiogenic or anti-tumor activities
by methods known in the art (Tolsma et al, J Cell Biol 122(2):
497-511, 1993; Tuszynski and Nicosia, Bioessays 18(1): 71-76,
1996).
[0067] The phrase "cyclooxygenase-2 inhibitors" or "COX-2
inhibitor" or "cyclooxygenase-II inhibitor" includes agents that
specifically inhibit a class of enzymes, cyclooxygenase-2, without
significant inhibition of cyclooxygenase-1. Preferably, it includes
compounds which have a cyclooxygenase-2 IC.sub.50 of less than
about 0.2 .mu.M, and also have a selectivity ratio of
cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at
least 50, and more preferably of at least 100. Even more
preferably, the compounds have a cyclooxygenase-1 IC.sub.50 of
greater than about 1 .mu.M, and more preferably of greater than 10
.mu.M.
[0068] Studies indicate that prostaglandins synthesized by
cyclooxygenases play a critical role in the initiation and
promotion of cancer. Moreover, COX-2 is overexpressed in neoplastic
lesions of the colon, breast, lung, prostate, esophagus, pancreas,
intestine, cervix, ovaries, urinary-bladder, and head & neck.
In several in vitro and animal models, COX-2 inhibitors have
inhibited tumor growth and metastasis. Non-limiting examples of
Cox-2 inhibitors include rofecoxib and JTE-522.
[0069] The phrase "matrix metalloproteinase inhibitor" or "MMP
inhibitor" includes agents that specifically inhibit a class of
enzymes, the zinc metalloproteinases (metalloproteases). The zinc
metalloproteinases are involved in the degradation of connective
tissue or connective tissue components. These enzymes are released
from resident tissue cells and/or invading inflammatory or tumor
cells. Blocking the action of zinc metalloproteinases interferes
with the creation of paths for newly forming blood vessels to
follow. Examples of MMP inhibitors are described in Golub, LM,
Inhibition of Matrix Metalloproteinases: Therapeutic Applications
(Annals of the New York Academy of Science, Vol 878). Robert A.
Greenwald and Stanley Zucker (Eds.), June 1999), and is hereby
incorporated by reference.
[0070] The phrase "integrin antagonist" includes agents that impair
endothelial cell adhesion via the various integrins. Integrin
antagonists induce improperly proliferating endothelial cells to
die, by interfering with molecules that blood vessel cells use to
bridge between a parent blood vessel and a tumor.
[0071] Adhesion forces are critical for many normal physiological
functions. Disruptions in these forces, through alterations in cell
adhesion factors, are implicated in a variety of disorders,
including cancer, stroke, osteoporosis, restenosis, and rheumatoid
arthritis (A. F. Horwitz, Scientific American, 276:(5): 68-75,
1997).
[0072] Integrins are a large family of cell surface glycoproteins
which mediate cell adhesion and play central roles in many adhesion
phenomena. Integrins are heterodimers composed of noncovalently
linked alpha and beta polypeptide subunits. Currently eleven
different alpha subunits have been identified and six different
beta subunits have been identified. The various alpha subunits can
combine with various beta subunits to form distinct integrins.
[0073] One integrin known as a.sub.vb.sub.3 (or the vitronectin
receptor) is normally associated with endothelial cells and smooth
muscle cells. A.sub.vb.sub.3 integrins can promote the formation of
blood vessels (angiogenesis) in tumors. These vessels nourish the
tumors and provide access routes into the bloodstream for
metastatic cells.
[0074] The phrase "integrin antagonist" includes agents that impair
endothelial cell adhesion via the various integrins. Integrin
antagonists induce improperly proliferating endothelial cells to
die, by interfering with molecules that blood vessel cells use to
bridge between a parent blood vessel and a tumor.
[0075] Adhesion forces are critical for many normal physiological
functions. Disruptions in these forces, through alterations in cell
adhesion factors, are implicated in a variety of disorders,
including cancer, stroke, osteoporosis, restenosis, and rheumatoid
arthritis (A. F. Horwitz, Scientific American, 276:(5): 68-75,
1997).
[0076] Integrins are a large family of cell surface glycoproteins
which mediate cell adhesion and play central roles in many adhesion
phenomena. Integrins are heterodimers composed of noncovalently
linked alpha and beta polypeptide subunits. Currently eleven
different alpha subunits have been identified and six different
beta subunits have been identified. The various alpha subunits can
combine with various beta subunits to form distinct integrins.
[0077] One integrin known as a.sub.vb.sub.3 (or the vitronectin
receptor) is normally associated with endothelial cells and smooth
muscle cells. A.sub.vb.sub.3 integrins can promote the formation of
blood vessels (angiogenesis) in tumors. These vessels nourish the
tumors and provide access routes into the bloodstream for
metastatic cells.
[0078] The a.sub.vb.sub.3 integrin is also known to play a role in
various other disease states or conditions including tumor
metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's
disease, humoral hypercalcemia of malignancy, angiogenesis,
including tumor angiogenesis, retinopathy, arthritis, including
rheumatoid arthritis, periodontal disease, psoriasis, and smooth
muscle cell migration (e.g. restenosis).
[0079] Tumor cell invasion occurs by a three step process: 1) tumor
cell attachment to extracellular matrix; 2) proteolytic dissolution
of the matrix; and 3) movement of the cells through the dissolved
barrier. This process can occur repeatedly and can result in
metastases at sites distant from the original tumor.
[0080] The a.sub.vb.sub.3 integrin and a variety of other
a.sub.v-containing integrins bind to a number of Arg-Gly-Asp (RGD)
containing matrix macromolecules. Compounds containing the RGD
sequence mimic extracellular matrix ligands and bind to cell
surface receptors. Fibronectin and vitronectin are among the major
binding partners of a.sub.vb.sub.3 integrin. Other proteins and
peptides also bind the a.sub.vb.sub.3 ligand. These include the
disintegrins (M. Pfaff et al., Cell Adhes. Commun. 2(6): 491-501,
1994), peptides derived from phage display libraries (Healy, J. M.
et al., Protein Pept. Lett. 3(1): 23-30, 1996; Hart, S. L. et al.,
J. Biol. Chem. 269(17): 12468-12474, 1994) and small cyclic RGD
peptides (M. Pfaff et al., J. Biol. Chem., 269(32): 20233-20238,
1994). The monoclonal antibody LM609 is also an a.sub.vb.sub.3
integrin antagonist (D. A. Cheresh et al., J. Biol. Chem., 262(36):
17703-17711, 1987).
[0081] A.sub.vb.sub.3 inhibitors are being developed as potential
anti-cancer agents. Compounds that impair endothelial cell adhesion
via the a.sub.vb.sub.3 integrin induce improperly proliferating
endothelial cells to die.
[0082] The a.sub.vb.sub.3 integrin has been shown to play a role in
melanoma cell invasion (Seftor et al., Proc. Natl. Acad. Sci. USA,
89: 1557-1561, 1992). The a.sub.vb.sub.3 integrin expressed on
human melanoma cells has also been shown to promote a survival
signal, protecting the cells from apoptosis (Montgomery et al.,
Proc. Natl. Acad. Sci. USA, 91: 8856-8860, 1994).
[0083] Mediation of the tumor cell metastatic pathway by
interference with the a.sub.vb.sub.3 integrin cell adhesion
receptor to impede tumor metastasis would be beneficial.
Antagonists of a.sub.vb.sub.3 have been shown to provide a
therapeutic approach for the treatment of neoplasia (inhibition of
solid tumor growth) because systemic administration of
a.sub.vb.sub.3 antagonists causes dramatic regression of various
histologically distinct human tumors (Brooks et al., Cell, 79:
1157-1164, 1994).
[0084] The adhesion receptor identified as integrin a.sub.vb.sub.3
is a marker of angiogenic blood vessels in chick and man. This
receptor plays a critical role in angiogenesis or
neovascularization. Angiogenesis is characterized by the invasion,
migration and proliferation of smooth muscle and endothelial cells
by new blood vessels. Antagonists of a.sub.vb.sub.3 inhibit this
process by selectively promoting apoptosis of cells in the
neovasculature. The growth of new blood vessels, also contributes
to pathological conditions such as diabetic retinopathy (Adonis et
al., Amer. J. Ophthal., 118: 445-450, 1994) and rheumatoid
arthritis (Peacock et al., J. Exp. Med., 175:, 1135-1138, 1992).
Therefore, a.sub.vb.sub.3 antagonists can be useful therapeutic
targets for treating such conditions associated with
neovascularization (Brooks et al., Science, 264: 569-571,
1994).
[0085] The a.sub.vb.sub.3 cell surface receptor is also the major
integrin on osteoclasts responsible for the attachment to the
matrix of bone. Osteoclasts cause bone resorption and when such
bone resorbing activity exceeds bone forming activity, osteoporosis
(a loss of bone) results, which leads to an increased number of
bone fractures, incapacitation and increased mortality. Antagonists
of a.sub.vb.sub.3 have been shown to be potent inhibitors of
osteoclastic activity both in vitro (Sato et al., J. Cell. Biol.,
111: 1713-1723, 1990) and in vivo (Fisher et al., Endocrinology,
132: 1411-1413, 1993). Antagonism of a.sub.vb.sub.3 leads to
decreased bone resorption and therefore assists in restoring a
normal balance of bone forming and resorbing activity. Thus it
would be beneficial to provide antagonists of osteoclast
a.sub.vb.sub.3 which are effective inhibitors of bone resorption
and therefore are useful in the treatment or prevention of
osteoporosis.
[0086] PCT Int. Appl. WO 97/08145 by Sikorski et al., discloses
meta-guanidine, urea, thiourea or azacyclic amino benzoic acid
derivatives as highly specific a.sub.vb.sub.3 integrin
antagonists.
[0087] PCT Int. Appl. WO 96/00574 A1 960111 by Cousins, R. D. et.
al., describe preparation of
3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine and -2-benzazepine
derivatives and analogs as vitronectin receptor antagonists.
[0088] PCT Int. Appl. WO 97/23480 A1 970703 by Jadhav, P. K. et.
al. describe annelated pyrazoles as novel integrin receptor
antagonists. Novel heterocycles including
3-[1-[3-(imidazolin-2-ylamino)propyl]indazol-
-5-ylcarbonylamino]-2-(benzyl oxycarbonylamino)propionic acid,
which are useful as antagonists of the a.sub.vb.sub.3 integrin and
related cell surface adhesive protein receptors.
[0089] PCT Int. Appl. WO 97/26250 A1 970724 by Hartman, G. D. et
al., describe the preparation of arginine dipeptide mimics as
integrin receptor antagonists. Selected compounds were shown to
bind to human integrin a.sub.vb.sub.3 with EIB <1000 nM and
claimed as compounds, useful for inhibiting the binding of
fibrinogen to blood platelets and for inhibiting the aggregation of
blood platelets.
[0090] PCT Int. Appl. WO 97/23451 by Diefenbach, B. et. al.
describe a series of tyrosine-derivatives used as alpha v-integrin
inhibitors for treating tumors, osteoporosis, osteolytic disorder
and for suppressing angiogenesis.
[0091] PCT Int. Appl. WO 96/16983 A1 960606. by Vuori, K. and
Ruoslahti, E. describe cooperative combinations of a.sub.vb.sub.3
integrin ligand and second ligand contained within a matrix, and
use in wound healing and tissue regeneration. The compounds contain
a ligand for the a.sub.vb.sub.3 integrin and a ligand for the
insulin receptor, the PDGF receptor, the IL-4 receptor, or the IGF
receptor, combined in a biodegradable polymeric (e.g. hyaluronic
acid) matrix.
[0092] PCT Int. Appl. WO 97/10507 A1 970320 by Ruoslahti, E; and
Pasqualini, R. describe peptides that home to a selected organ or
tissue in vivo, and methods of identifying them. A brain-homing
peptide, nine amino acid residues long, for example, directs red
blood cells to the brain. Also described is use of in vivo panning
to identify peptides homing to a breast tumor or a melanoma.
[0093] PCT Int. Appl. WO 96/01653 A1 960125 by Thorpe, Philip E.;
Edgington, Thomas S. describes bifunctional ligands for specific
tumor inhibition by blood coagulation in tumor vasculature. The
disclosed bispecific binding ligands bind through a first binding
region to a disease-related target cell, e.g. a tumor cell or tumor
vasculature; the second region has coagulation-promoting activity
or is a binding region for a coagulation factor. The disclosed
bispecific binding ligand may be a bispecific (monoclonal)
antibody, or the two ligands may be connected by a (selectively
cleavable) covalent bond, a chemical linking agent, an
avidin-biotin linkage, and the like. The target of the first
binding region can be a cytokine-inducible component, and the
cytokine can be released in response to a leukocyte-activating
antibody; this may be a bispecific antibody which crosslinks
activated leukocytes with tumor cells.
[0094] Nonlimiting examples of integrin antagonists that may be
used in the present invention are identified in Table 1, below.
1TABLE NO. 1 Examples of Integrin antagonists Trade/ Research Mode
of Compound Name Action Reference Dosage
2(S)-Benzenesulfonamido)-3-[4-[2- L-748415 Vitronectin
(3,4,5,6-tetrahydropyrimidin-2- antagonist
ylamino)ethoxy]benzamido]propionic acid Merk KGaA Compound I25
Ethyl beta-[[2-[[[3- Vitronectin WO 97/08145
[(3,4,5,6,-tetrahydro-2H- antagonist
azepin-7-yl)amino]phenyl]carbonyl]amino]acetyl]-
amino]pyridine-3-propanoic acid O-[9,10-dimethoxy-1,2,3,4,5,6-
Vitronectin WO 97/34865 hexahydro-4-[(1,4,5,6- antagonist
tetrahydro-2- pyrimidinyl)hydrazono]-8- benz(e)azulenyl]-N-
[(phenylmethoxy)carbonyl]-DL- homoserine 2,3-dihydroxypropyl ester
(2S)-Benzoylcarbonyl amino-3-[2- Vitronectin EP 796855
((4S)-(3-(4,5-dihydro-1H- antagonist imidazol-2-ylamino)-propyl)-
2,5-dioxo-imidazolidin-1- yl)-acetylamino]-propionate S-836
Vitronectin antagonist; Angiogenesis inhibitor; solid tumors
(S)-2-[7-[N-(Benzimidazol- SB-223245 Vitronectin
2-ylmethyl)-N-methylcarbamoyl]- antagonist;
4-methyl-3-oxo-2,3,4,5-tetrahydro-1H- Angiogenesis
1,4-benzodiazepin-2-yl]acetic acid inhibitor SD-983 Vitronectin
antagonist; Angiogenesis inhibitor Isoxaoline Vitronectin WO
96/37492 0.001-10 derivatives receptor mg/kg/day; antagonist
0.01-0.5 (pref. 0.01-0.1) mg/kg/day intra- nasally
(2S)-Bensoylcarbonyl amino-3-[2- Vitronectin EP 796855
((4S)-(3-(4,5-dihydro-1H-imidazol-2- antagonist
ylamino)-propyl)-2,5-dioxo-imidazolindin- 1-yl)-acetylamino]-propi-
onate Benzazulene deriviatives; Vitronectin WO 97/34865
O-[9,10-dimethoxy-1,2,3,4,5,6- antagonist hexahydro-4-[(1,4,5,6-t-
etrahydro-2- pyrimidinyl)hydrazono]-8- benz(e)azzulenyl]-N-
[(phenylmethoxy)carbonyl]-DL- homoserine 2,3-dihydroxypropyl ester
Immunoglobulin G, (human-mouse abcix- GPIIb IIIa Recomended
monoclonal c7E3 clone p7E3VHhC imab; receptor dosage: gamma 4 Fab
fragment anti- ReoPro antagonist; Intra- human glycoprotein
IIb/IIIa Vitronectin venous receptor), disulfide with antagonist
bolus of human-mouse monoclonal c7E3 0.25 clone p7E3VkhCk light
chain- mg/kg, followed by 10 .mu.g/min for 12 hrs.
Arg-Gly-Asp-D-phe-Val cRGDfV Apoptosis penta- agonist; peptide
Vitronectin antagonist vitro- Vitronectin Orally nectin antagonist
active antag- onist
[0095] Further examples of integrin antagonists can be found in the
following documents:
2 WO 98/07432 WO 98/16227 WO 97/36862 WO 97/36861 WO 97/36860 WO
9736859 WO 97/36858 US 5639765 WO 97/08145 US 5639765 WO 98/22500
WO 98/20897 WO 98/18764 WO 98/14192 WO 98/08840 WO 98/04913 WO
97/48395 WO 9744333 WO 98/00395 WO 97/41102 WO 97/34865 WO 97/39028
WO 97/37655 WO 97/33887 EP 796855 WO 97/26250 WO 97/24124 WO
97/24122 WO 97/24336 WO 97/24119 WO 97/23480 WO 97/23451 EP 765660
WO 97/14716 EP 77/1818 WO 97/01540 WO 96/37492 EP 741133 US 5565449
WO 96/26190 EP 727425 US 5627197 DE 4439846 EP 711770 EP 710657 WO
96/06087 WO 96/00730 WO 96/00574 WO 95/23811 US 5464855 WO 95/28426
JP 07242645 JP 07206860 EP 645376 WO 95/07712 WO 95/00544 AU
9464771 EP 614664 WO 94/21607 WO 94/15936 JP 06128289 WO 9411739 WO
93/08174 EP 537654 EP 529858 US 5229366 WO 92/07870 WO 92/00995 EP
381033 WO 98/08518 US 5721210 EP 820991 EP 820988 WO 97/48444 WO
97/41844 WO 97/45447 WO 97/45137 US 5686570 US 5686568 US 5686571
US 5686569 US 5686567 US 5686566 WO 97/41149 DE 19613933 WO
97/35615 WO 97/25031 US 5639726 WO 97/18838 WO 97/11718 US 5612311
EP 77/0622 WO 97/08203 WO 97/06791 WO 97/03094 WO 96/40781 WO
96/40250 US 5536814 US 5510332 WO 96/07734 WO 96/05304 WO 96/00581
WO 95/34641 WO 95/30438 DE 4415310 EP 668278 EP 656348 DE 4336758
EP 623615 DE 4310643 AU 9459185 WO 94/01152 CA 2120303 EP 632053 EP
618225 WO 94/18981 WO 94/13310 JP 06116289 WO 94/05310 EP 58/9181
EP 589181 US 5491129 WO 93/25218 WO 93/20229 US 5225531 EP 570352
EP 570352 WO 92/09200 WO 91/15515 EP 445796 WO 91/07977 EP 410767
US 5061693 EP 384362 US 5663297 EP 372486 US 5039805 WO 9003983 WO
89/05155 DE 19548798 DE 19626701 DE 19653645 DE 9653646 DE 19653647
DE 19654483 DE 4439846 EP 683173 EP 537654 EP 645376 EP 0710657 EP
727425 EP 741133 EP 771565 EP 0846702 EP 853084 JP 07285992 JP
08337523 JP 09169742 JP 9235239 JP 09316000 JP 10045587 JP 08183752
JP 183788 US 5574026 WO 95/14714 WO 9525543 WO 95/28426 WO 95/32710
WP 96/06087 WO 96/26190 WO 96/32945 WO 97/12625 WO 97/15666 WO
97/16197 WO 97/21726 WO 97/22596 WO 97/23625 WO 97/24336 WO
98/25892 WO 98/25601 WO 97/26258 WO 97/33576 WO 98/00144 WO
98/00395 WO 98/03573 WO 98/08518 WO 98/08840 WO 98/10795 WO
98/11089 WO 98/11223 WO 98/12226 WO 98/13071 WO 98/13350 WO
98/13354 WO 98/14192 WO 98/15278 WO 98/15574 WO 98/18460 WO
98/18461 WO 98/18764 WO 98/21230 WO 98/23608 WO 98/23613
[0096] The following individual references each hereby incorporated
by reference herein, describe various integrin antagonists suitable
for use in the invention described herein, and processes for their
manufacture:
3 WO 98/07432 WO 98/16227 WO 97/36862 WO 97/36861 WO 97/36860 WO
97/36859 WO 97/36858 US 5639765 WO 97/08145 US 5639765 WO 98/22500
WO 98/20897 WO 98/18764 WO 98/14192 WO 98/08840 WO 98/04913 WO
97/48395 WO 97/44333 WO 98/00395 WO 97/41102 WO 97/34865 WO
97/39028 WO 97/37655 WO 97/33887 EP 79/6855 WO 97/26250 WO 97/24124
WO 97/24122 WO 97/24336 WO 97/24119 WO 97/23480 WO 97/23451 EP
76/5660 WO 97/14716 EP 771818 WO 97/01540 WO 96/37492 EP 74/1133 US
5565449 WO 96/26190 EP 72/7425 US 5627197 DE 4439846 EP 711770 EP
71/0657 WO 96/06087 WO 96/00730 WO 96/00574 WO 95/23811 US 5464855
WO 95/28426 JP 07242645 JP 07/206860 EP 64/5376 WO 95/07712 WO
95/00544 AU 94/64771 EP 61/4664 WO 94/21607 WO 94/15936 JP
06/128289 WO 94/11739 WO 93/08174 EP 537654 EP 52/9858 US 52/29366
WO 92/07870 WO 92/00995 EP 38/1033 WO 98/08518 US 572,210 EP 820991
EP 82/0988 WO 97/48444 WO 97/41844 WO 97/45447 WO 97/45137 US
5686570 US 5686568 US 5686571 US 5686569 US 5686567 US 5686566 WO
97/41149 DE 19/613933 WO 97/35615 WO 97/25031 US 5639726 WO
97/18838 WO 97/11718 US 5612311 EP 770622 WO 97/08203 WO 97/06791
WO 97/03094 WO 96/40781 WO 96/40250 US 5536814 US 5510332 WO
96/07734 WO 96/05304 WO 96/00581 WO 95/34641 WO 95/30438 DE
44/15310 EP 66/8278 EP 656348 DE 4336758 EP 62/3615 DE 43/10643 AU
94/59185 NO 94/01152 CA 21/20303 EP 63/2053 EP 618225 WO 94/18981
WO 94/13310 JP 06/116289 WO 94/05310 EP 58/9181 EP 58/9181 US
5491129 WO 93/25218 WO 93/20229 U.S. 5225531 EP 570352 EP 57/0352
WO 92/09200 WO 91/15515 EP 445796 WO 91/07977 EP 410767 US 5061693
EP 384362 US 5,63297 EP 37/2486 US 5039805 WO 90/03983 WO 89/05155
DE 19548798 DE 19/626701 DE 19653645 DE 19653646 DE 19653647 DE
19/654483 DE 4439846 EP 683173 EP 537654 EP 0/645376 EP 0710657 EP
727425 EP 741133 EP 0/771565 EP 0846702 EP 853084 JP 07285992 JP
08/337523 JP 09169742 JP 09235239 JP 09316000 JP 10/045587 JP
08183752 JP 08183788 US 5574026 WO 95/14714 WO 95/25543 WO 95/28426
WO 95/32710 WP 96/06087 WO 96/26190 WO 96/32945 WO 97/12625 WO
97/15666 WO 97/16197 WO 97/21726 WO 97/22596 WO 97/23625 WO
97/24336 WO 98/25892 WO 98/25601 WO 97/26258 WO 97/33576 WO
98/00144 WO 98/00395 WO 98/03573 WO 98/08518 WO 98/08840 WO
98/10795 WO 98/11089 WO 98/11223 WO 98/12226 WO 98/13071 WO
98/13350 WO 98/13354 WO 98/14192 WO 98/15278 WO 98/15574 WO
98/18460 WO 98/18461 WO 98/18764 WO 98/21230 WO 98/23608 WO
98/23613
[0097] The following individual references each hereby incorporated
by reference herein, describe additional integrin antagonists
suitable for use in the invention described herein, and processes
for their manufacture:
4 WO 99/50249 WO 99/45927 WO 99/44994 US 5955572 US 59552341 WO
99/38849 WO 99/37683 WO 99/37621 WO 99/33798 EP 928793 US 5925655
US 5919792 WO 99/32457 WO 99/31099 US 5912234 WO 99/31061 WO
99/31061 WO 99/30713 WO 99/30709 WO 99/26945 WO 99/15508 WO
99/15507 WO 99/15506 WO 99/15178 WO 99/15170 WO 99/11626 WO
99/06049 WO 99/05107 US 5852210 US 5843906 WO 98/54217 US 5840961
WO 98/43962 US 5773646 US 5773644 WO 98/33919 WO 98/31359 WO
98/30542 EP 854145 EP 854140 EP 853084 US 5773412 US 5766591 US
5760028 US 5759996 WO 98/15278 US 5741796 WO 98/10795 WO
97/08145
[0098] The Vitaxin used in the therapeutic combinations of the
present invention can be prepared in the manner set forth in WO
98/33,919.
[0099] Some Preferred integrin antagonists that may be used in the
present invention are listed in the following references hereby
each individually incorporated by reference, herein: U.S. Pat. No.
5,773,644; U.S. Pat. No. 5,773,646; U.S. patent application Ser.
No. 09/289,140; U.S. Pat. No. 5,852,210; U.S. Pat. No. 5,843,906;
U.S. patent application Ser. No. 09/141,547; U.S. Pat. No.
5,952,381; U.S. patent application No. 09/288,742; U.S. patent
application Ser. No. 60/003,277; U.S. patent application Ser. No.
U.S. 08/713,555; U.S. patent application Ser. No. 09/215,229; U.S.
patent application Ser. No. 09/034,758; U.S. patent application
Ser. No. 09/261,822; WO 98/33919.
[0100] More preferred integrin antagonists that may be used in the
present invention include, but are not limited to 1
[0101]
(3R)-N-[[5-((1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)amino]-3-py-
ridinyl]carbonyl)glycyl-3-(3-bromo-5-chloro-2-hydroxyphenyl)-b-alanine;
2
[0102]
(3R)-N-[[1,6-dihydro-6-oxo-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrim-
idinyl)amino]-3-pyridinyl]carbonyl]glycyl-3-(3-bromo-5-chloro-2-hydroxyphe-
nyl)-b-alanine; 3
[0103]
(3R)-N-[3-amino-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)amin-
o]benzoyl}glycyl-3-(3-bromo-5-chloro-2-hydroxyphenyl)-b-alanine;
4
[0104]
(3R)-N-[3-[(hydroxyamino)carbonyl]-5-[(1,4,5,6-tetrahydro-5-hydroxy-
)-2-pyrimidinyl)amino)benzoyl]glycyl-3-(3-bromo-5-chloro-2-hydroxyphenyl)--
b-alanine; 5
[0105] (3R)-N-[3-[(4-,
5-dihydro-1H-imidazol-2-yl)amino)benzoyl]glycyl-3-(-
3-bromo-5-chloro-2-hydroxyphenyl)-b-alanine; 6
[0106]
(3R)-N-[3-[(aminoiminomethyl)amino]benzoyl]glycyl-3-(3-bromo-5-chlo-
ro-2-hydroxyphenyl)-b-alanine; 7
[0107]
(3R)-N-[3-hydroxy-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)am-
ino]benzoyl)glycyl-3-(3-bromo-5-chloro-2-hydroxyphenyl)-b-alanine;
8
[0108]
(3R)-N-[3-hydroxy-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)am-
ino]benzoyl]glycyl-3-(3,5-dichloro-2-hydroxyphenyl)-b-alanine;
9
[0109]
(3R)-N-[3-hydroxy-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)am-
ino]benzoyl]glycyl-3-(5-bromo-3-chloro-2-hydroxyphenyl)-b-alanine;
10
[0110]
(3R)-N-[3-hydroxy-5-[(1,4,5,6-tetrahydro-5-hydroxy-2-pyrimidinyl)am-
ino]benzoyl]glycyl-3-(3-bromo-5-chloro-2-hydroxyphenyl)-b-alanine;
11
[0111]
b-[3-([(3-[[4,5-dihydro-1H-imidazol-2-yl)amino]phenyl]sulfonyl]amin-
o]phenyl]-3,5-difluorobenzenepropanoic acid; 12
[0112]
3,5-difluoro-b-[3-[[[3-[(1,4,5,6-tetrahydro-2-pyrimidinyl)amino]ben-
zoyl]amino]methyl]phenyl]benzenepropanoic acid; 13 14
[0113]
(2E)-3-[3-ethyl-4-[[3-[(1,4,5,6-tetrahydro-2-pyrimidinyl)amino]benz-
oyl]amino]phenyl]-2-propenoic acid; 15
[0114]
(2E)-3-[3-[2-[3-[(4,5-dihydro-1H-imidazol-2-yl)amino]phenyl]-2-oxoe-
thoxy]phenyl]-2-propenoic acid; 16
[0115]
(10S)-10,11-dihydro-3-[3-(2-pyridinylamino)propoxy]-5H-dibenzo[a,d]-
cycloheptene-10-acetic acid; 17
[0116]
(2S)-7-[[(1H-benzimidazol-2-ylmethyl)methylamino]carbonyl]-2,3,4,5--
tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid;
18
[0117]
(2S)-2,3,4,5-tetrahydro-4-methyl-7-[[[(5-methyl-1H-imidazo[4,5-b]py-
ridin-2-yl]methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetic
acid; 19
[0118]
(bR)-b-[[[(3R)-2-oxo-3-[2-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl-
)ethyl]-1-pyrrolidinyl]acetyl]amino]-1H-indole-3-pentanoic acid;
20
[0119] I24) Vitaxin antibody(Ixsys);
[0120] I25) Merck KGaA EMD-121974, cyclo[RGDf-N(Me)V-]; 212223
[0121] Still more preferred integrin antagonists include but are
not limited to 24
[0122]
(10S)-10,11-dihydro-3-[3-(2-pyridinylamino)propoxy]-5H-dibenzo[a,d]-
cycloheptene-10-acetic acid; 25
[0123]
(2S)-7-[[(1H-benzimidazol-2-ylmethyl)methylamino]carbonyl]-2,3,4,5--
tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid;
26
[0124]
(2S)-2,3,4,5-tetrahydro-4-methyl-7-[[[(5-methyl-1H-imidazo[4,5-b]py-
ridin-2-yl]methyl]amino]carbonyl]-3-oxo-1H-1,4-benzodiazepine-2-acetic
acid; 27
[0125]
(bR)-b-[[[(3R)-2-oxo-3-[2-(1,5,6,7-tetrahydro-1,8-naphthyridin-2-yl-
)ethyl]-1-pyrrolidinyl]acetyl]amino]-1H-indole-3-pentanoic acid;
28
[0126] I24) Vitaxin antibody(Ixsys);
[0127] I25) Merck KGaA EMD-121974, cyclo[RGDf-N(Me)V-]; 29
[0128] The phrase "antineoplastic agents" includes agents that
exert antineoplastic effects, i.e., prevent the development,
maturation, or spread of neoplastic cells, directly on the tumor
cell, e.g., by cytostatic or cytocidal effects, and not indirectly
through mechanisms such as biological response modification. There
are large numbers of antineoplastic agents available in commercial
use, in clinical evaluation and in pre-clinical development, which
could be included in the present invention for treatment of
neoplasia by combination drug chemotherapy. For convenience of
discussion, antineoplastic agents are classified into the following
classes, subtypes and species:
[0129] ACE inhibitors,
[0130] alkylating agents,
[0131] angiogenesis inhibitors,
[0132] angiostatin,
[0133] anthracyclines/DNA intercalators,
[0134] anti-cancer antibiotics or antibiotic-type agents,
[0135] antimetabolites,
[0136] antimetastatic compounds,
[0137] asparaginases,
[0138] bisphosphonates,
[0139] cGMP phosphodiesterase inhibitors,
[0140] calcium carbonate,
[0141] cyclooxygenase-2 inhibitors
[0142] DHA derivatives,
[0143] DNA topoisomerase,
[0144] endostatin,
[0145] epipodophylotoxins,
[0146] genistein,
[0147] hormonal anticancer agents,
[0148] hydrophilic bile acids (URSO),
[0149] immunomodulators or immunological agents,
[0150] integrin antagonists
[0151] interferon antagonists or agents,
[0152] MMP inhibitors,
[0153] miscellaneous antineoplastic agents,
[0154] monoclonal antibodies,
[0155] nitrosoureas,
[0156] NSAIDs,
[0157] ornithine decarboxylase inhibitors,
[0158] pBATTs,
[0159] radio/chemo sensitizers/protectors,
[0160] retinoids
[0161] selective inhibitors of proliferation and migration of
endothelial cells,
[0162] selenium,
[0163] stromelysin inhibitors,
[0164] taxanes,
[0165] vaccines, and
[0166] vinca alkaloids.
[0167] The major categories that some preferred antineoplastic
agents fall into include antimetabolite agents, alkylating agents,
antibiotic-type agents, hormonal anticancer agents, immunological
agents, interferon-type agents, and a category of miscellaneous
antineoplastic agents. Some antineoplastic agents operate through
multiple or unknown mechanisms and can thus be classified into more
than one category.
[0168] A first family of antineoplastic agents which may be used in
combination with the present invention consists of
antimetabolite-type antineoplastic agents. Antimetabolites are
typically reversible or irreversible enzyme inhibitors, or
compounds that otherwise interfere with the replication,
translation or transcription of nucleic acids. Suitable
antimetabolite antineoplastic agents that may be used in the
present invention include, but are not limited to acanthifolic
acid, aminothiadiazole, anastrozole, bicalutamide, brequinar
sodium, capecitabine, carmofur, Ciba-Geigy CGP-30694, cladribine,
cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine
conjugates, cytarabine ocfosfate, Lilly DATHF, Merrel Dow DDFC,
dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi
DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015,
fazarabine, finasteride, floxuridine, fludarabine phosphate,
N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152,
fluorouracil (5-FU), 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly
LY-188011, Lilly LY-264618, methobenzaprim, methotrexate, Wellcome
MZPES, nafarelin, norspermidine, nolvadex, NCI NSC-127716, NCI
NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,
pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC,
stearate; Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF,
trimetrexate, tyrosine kinase inhibitors, tyrosine protein kinase
inhibitors, Taiho UFT, toremifene, and uricytin.
[0169] Preferred antimetabolite agents that may be used in the
present invention include, but are not limited to, those identified
in Table No. 1, below.
5TABLE NO. 1 Antimetabolite agents Common Name/ Compound Trade Name
Company Reference Dosage 1,3- anastrozole; Zeneca EP 296749
1-mg/day Benzenediacetonitrile,alpha,alpha,alpha',alpha'- ARIMIDEX
.RTM. tetramethyl-5-(1H-1,2,4- triazol-1-ylmethyl)-
Propanamide,N-[4-cyano-3- bicalutamide; Zeneca EP 100172 50 mg once
(trifluoromethyl)phenyl]-3- CASODEX .RTM. daily
[(4-fluorophenyl)sulfonyl]-2- hydroxy-2-methyl-,(+/-)- capecitabine
Roche U.S. Pat. No. 5472949 Adenosine,2-chloro-2'- cladribine;
Johnson & EP 173059 0.09 deoxy-; 2-chloro-2'- 2-CdA; Johnson
mg/kg/day deoxy-(beta)-D-adenosine) LEUSTAT; for 7 LEUSTATIN .RTM.;
days. LEUSTA-TIN .RTM. in-jection; LEUSTATINE .RTM.; RWJ-26251;
2(1H)-Pyrimidinone,4-amino-1-[5-O- cytarabine Yamasa Corp EP 239015
100-300 [hydroxy(octadecyloxy)phosphinyl]- ocfosfate; mg/day for
beta-D-arabinofuranosyl]-,monosodium salt ara CMP 2 weeks stearyl
ester; C- 18-PCA; cytarabine phosphate stearate; Starasid; YNK-01;
CYTOSAR-U .RTM. 4-Azaandrost-1-ene-17-carboxamide,N- finasteride;
Merck & Co EP 155096
(1,1-dimethylethyl)-3-oxo-,(5alpha,17beta)- PROPECIA .RTM.
fluorouracil U.S. Pat. No. 4336381 (5-FU) Fludarabine phosphate.
9H-Purin-6- fludarabine Southern U.S. Pat. No. 4357324 25
mg/m.sup.2/d amine,2-fluoro-9-(5-O-phosphono- phosphate; Research
IV over a beta-D-arabinofuranosyl) 2-F-araAMP; Institute; period of
Fludara; Berlex approximately Fludara iv; 30 minutes Fludara Oral;
daily for NSC-312887; 5 con- SH-573; secutive SH-584; days, SH-586;
commenced every 28 days. gemcitabine Eli Lily U.S. Pat. No. 4526988
N-(4-(((2,4- methotrexate Hyal U.S. Pat. No. 2512572 tropho-
diamino-6- iv, Hyal; Pharma- blastic
pteridinyl)methyl)methylamino)benzoyl)- HA + ceutical; diseases:
L-glutamic acid methotrexate, American 15 to 30 Hyal; Home mg/d
methotrexate Products; orally or iv, HIT Lederle intra- Technolog;
muscularly in a five- day course (repeated 3 to 5 times as needed)
Luteinizing hormone- nafarelin Roche EP 21234 releasing
factor(pig),6-[3-(2- naphthalenyl)-D-alanine]- pentostatin; Warner-
U.S. Pat. No. 3923785 CI-825; Lambert DCF; deoxycoformycin; Nipent;
NSC-218321; Oncopent; Ethanamine,2-[4-(4-chloro- toremifene; Orion
EP 95875 60 mg/d 1,2-diphenyl-1-butenyl)phenoxy]- FARESTON .RTM.
Pharma N,N-dimethyl-,(Z)-
[0170] A second family of antineoplastic agents which may be used
in combination with the present invention consists of
alkylating-type antineoplastic agents. The alkylating agents are
believed to act by alkylating and cross-linking guanine and
possibly other bases in DNA, arresting cell division. Typical
alkylating agents include nitrogen mustards, ethyleneimine
compounds, alkyl sulfates, cisplatin, and various nitrosoureas. A
disadvantage with these compounds is that they not only attack
malignant cells, but also other cells which are naturally dividing,
such as those of bone marrow, skin, gastro-intestinal mucosa, and
fetal tissue. Suitable alkylating-type antineoplastic agents that
may be used in the present invention include, but are not limited
to, Shionogi 254-S, aldo-phosphamide analogues, altretamine,
anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,
Wakunaga CA-102, carboplatin, carmustine (BiCNU), Chinoin-139,
Chinoin-153, chlorambucil, cisplatin, cyclophosphamide, American
Cyanamid CL-286558, Sanofi CY-233, cyplatate, dacarbazine, Degussa
D-19-384, Sumimoto DACHP(Myr)2, diphenylspiromustine, diplatinum
cytostatic, Erba distamycin derivatives, Chugai DWA-2114R, ITI E09,
elmustine, Erbamont FCE-24517, estramustine phosphate sodium,
etoposide phosphate, fotemustine, Unimed G-6-M, Chinoin GYKI-17230,
hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,
mitolactol, mycophenolate, Nippon Kayaku NK-121, NCI NSC-264395,
NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter
PTT-119, ranimustine, semustine, SmithKline SK&F-101772,
thiotepa, Yakult Honsha SN-22, spiromus-tine, Tanabe Seiyaku
TA-077, tauromustine, temozolomide, teroxirone, tetraplatin and
trimelamol.
[0171] Preferred alkylating agents that may be used in the present
invention include, but are not limited to, those identified in
Table No. 2, below.
6TABLE NO. 2 Alkylating agents Common Name/ Compound Trade Name
Company Reference Dosage Platinum,diammine[1,1- carboplatin;
Johnson U.S. Pat. No. 4657927. 360 mg/m
cyclobutanedicarboxylato(2-)]-,(SP-4-2)- PARAPLATIN .RTM. Matthey
U.S. Pat. No. 4140707. (squared) I.V. on day 1 every 4 weeks.
Carmustine,1,3-bis(2- BiCNU .RTM. Ben Venue JAMA 1985; Preferred:
chloroethyl)-1-nitro-sourea Labora- 253 (11): 150 to 200 tories,
1590-1592. mg/m.sup.2 Inc. every 6 wks. etoposide Bristol- U.S.
Pat. No. 4564675 phosphate Myers Squibb thiotepa
Platinum,diamminedi- cisplatin; Bristol- U.S. Pat. No. 4177263
chloro-,(SP-4-2)- PLATINOL-AQ Myers Squibb dacarbazine DTIC Dome
Bayer 2 to 4.5 mg/kg/day for 10 days; 250 mg/ square meter body
surface/ day I.V. for 5 days every 3 weeks ifosfamide IFEX Bristol-
4-5 g/m Meyers (square) Squibb single bolus dose, or 1.2-2 g/m
(square) I.V. over 5 days. cyclophosphamide U.S. Pat. No. 4537883
cis- Platinol Bristol- 20 mg/M.sup.2 diaminedichloroplatinum
Cisplatin Myers IV daily Squibb for a 5 day cycle.
[0172] A third family of antineoplastic agents which may be used in
combination with the present invention consists of antibiotic-type
antineoplastic agents. Suitable antibiotic-type antineoplastic
agents that may be used in the present invention include, but are
not limited to Taiho 4181-A, aclarubicin, actinomycin D,
actinoplanone, Erbamont ADR-456, aeroplysinin derivative, Ajinomoto
AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline,
azino-mycin-A, bisucaberin, Bristol-Myers BL-6859, Bristol-Myers
BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605,
Bristol-Myers BMY-27557, Bristol-Myers BMY-28438, bleomycin
sulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,
dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79,
Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC92-B,
ditrisarubicin B, Shionogi DOB-41, doxorubicin,
doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,
esorubicin, esperamicin-A1, esperamicin-Alb, Erbamont FCE-21954,
Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,
gregatin-A, grincamycin, herbimycin, idarubicin, illudins,
kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery
KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko
KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303,
menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, neoenactin,
Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SR1 International
NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin,
pirarubicin, porothramycin, pyrindamycin A, Tobishi RA-I,
rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, Sumitomo
SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,
sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical
SS-7313B, SS Pharmaceutical SS-9816B, steffimycin B, Taiho 4181-2,
talisomycin, Takeda TAN-868A, terpentecin, thrazine, tricrozarin A,
Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi
Y-25024 and zorubicin.
[0173] Preferred antibiotic anticancer agents that may be used in
the present invention include, but are not limited to, those agents
identified in Table No. 3, below.
7TABLE NO. 3 Antibiotic anticancer agents Common Name/ Compound
Trade Name Company Reference Dosage 4-Hexenoic acid,6-(1,3-
mycopheno- Roche WO 91/19498 1 to 3 gm/d dihydro-4-hydroxy-6- late
mofetil methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-,2-
(4-morpholinyl)ethyl ester,(E)- mitoxantrone U.S. Pat. No. 4310666
doxorubicin U.S. Pat. No. 3590028 Mitomycin Mutamycin Bristol-
After full and/or Myers hemato- mitomycin-C Squibb logical
Oncology/ recovery Immunology from any previous chemotherapy: 20
mg/m.sup.2 intravenously as a single dose via a functioning
intravenous catheter.
[0174] A fourth family of antineoplastic agents which may be used
in combination with the present invention consists of synthetic
nucleosides. Several synthetic nucleosides have been identified
that exhibit anticancer activity. A well known nucleoside
derivative with strong anticancer activity is 5-fluorouracil
(5-FU). 5-Fluorouracil has been used clinically in the treatment of
malignant tumors, including, for example, carcinomas, sarcomas,
skin cancer, cancer of the digestive organs, and breast cancer.
5-Fluorouracil, however, causes serious adverse reactions such as
nausea, alopecia, diarrhea, stomatitis, leukocytic
thrombocytopenia, anorexia, pigmentation, and edema. Derivatives of
5-fluorouracil with anti-cancer activity have been described in
U.S. Pat. No. 4,336,381. Further 5-FU derivatives have been
described in the following patents listed in Table No. 4, hereby
individually incorporated by reference herein.
8TABLE NO. 4 5-Fu derivatives JP 50-50383 JP 50-50384 JP 50-64281
JP 51-146482 JP 53-84981
[0175] U.S. Pat. No. 4,000,137 discloses that the peroxidate
oxidation product of inosine, adenosine, or cytidine with methanol
or ethanol has activity against lymphocytic leukemia. Cytosine
arabinoside (also referred to as Cytarabin, araC, and Cytosar) is a
nucleoside analog of deoxycytidine that was first synthesized in
1950 and introduced into clinical medicine in 1963. It is currently
an important drug in the treatment of acute myeloid leukemia. It is
also active against acute lymphocytic leukemia, and to a lesser
extent, is useful in chronic myelocytic leukemia and non-Hodgkin's
lymphoma. The primary action of araC is inhibition of nuclear DNA
synthesis. Handschumacher, R. and Cheng, Y., "Purine and Pyrimidine
Antimetabolites", Cancer Medicine, Chapter XV-1, 3rd Edition,
Edited by J. Holland, et al., Lea and Febigol, publishers.
[0176] 5-Azacytidine is a cytidine analog that is primarily used in
the treatment of acute myelocytic leukemia and myelodysplastic
syndrome.
[0177] 2-Fluoroadenosine-5'-phosphate (Fludara, also referred to as
FaraA) is one of the most active agents in the treatment of chronic
lymphocytic leukemia. The compound acts by inhibiting DNA
synthesis. Treatment of cells with F-araA is associated with the
accumulation of cells at the G1/S phase boundary and in S phase;
thus, it is a cell cycle S phase-specific drug. InCorp of the
active metabolite, F-araATP, retards DNA chain elongation. F-araA
is also a potent inhibitor of ribonucleotide reductase, the key
enzyme responsible for the formation of dATP.
2-Chlorodeoxyadenosine is useful in the treatment of low grade
B-cell neoplasms such as chronic lymphocytic leukemia,
non-Hodgkins' lymphoma, and hairy-cell leukemia. The spectrum of
activity is similar to that of Fludara. The compound inhibits DNA
synthesis in growing cells and inhibits DNA repair in resting
cells.
[0178] A fifth family of antineoplastic agents which may be used in
combination with the present invention consists of hormonal agents.
Suitable hormonal-type antineoplastic agents that may be used in
the present invention include, but are not limited to Abarelix;
Abbott A-84861; Abiraterone acetate; Aminoglutethimide;
anastrozole; Asta Medica AN-207; Antide; Chugai AG-041R; Avorelin;
aseranox; Sensus B2036-PEG; Bicalutamide; buserelin; BTG CB-7598;
BTG CB-7630; Casodex; cetrolix; clastroban; clodronate disodium;
Cosudex; Rotta Research CR-1505; cytadren; crinone; deslorelin;
droloxifene; dutasteride; Elimina; Laval University EM-800; Laval
University EM-652; epitiostanol; epristeride; Mediolanum EP-23904;
EntreMed 2-ME; exemestane; fadrozole; finasteride; flutamide;
formestane; Pharmacia & Upjohn FCE-24304; ganirelix; goserelin;
Shire gonadorelin agonist; Glaxo Wellcome GW-5638; Hoechst Marion
Roussel Hoe-766; NCI hCG; idoxifene; isocordoin; Zeneca ICI-182780;
Zeneca ICI-118630; Tulane University J015X; Schering Ag J96;
ketanserin; lanreotide; Milkhaus LDI-200; letrozol; leuprolide;
leuprorelin; liarozole; lisuride hydrogen maleate; loxiglumide;
mepitiostane; Leuprorelin; Ligand Pharmaceuticals LG-1127; LG-1447;
LG-2293; LG-2527; LG-2716; Bone Care International LR-103; Lilly
LY-326315; Lilly LY-353381-HCl; Lilly LY-326391; Lilly LY-353381;
Lilly LY-357489; miproxifene phosphate; Orion Pharma MPV-2213ad;
Tulane University MZ-4-71; nafarelin; nilutamide; Snow Brand NKS01;
octreotide; Azko Nobel ORG-31710; Azko Nobel ORG-31806; orimeten;
orimetene; orimetine; ormeloxifene; osaterone; Smithkline Beecham
SKB-105657; Tokyo University OSW-1; Peptech PTL-03001; Pharmacia
& Upjohn PNU-156765; quinagolide; ramorelix; Raloxifene;
statin; sandostatin LAR; Shionogi S-10364; Novartis SMT-487;
somavert; somatostatin; tamoxifen; tamoxifen methiodide; teverelix;
toremifene; triptorelin; TT-232; vapreotide; vorozole; Yamanouchi
YM-116; Yamanouchi YM-511; Yamanouchi YM-55208; Yamanouchi
YM-53789; Schering AG ZK-1911703; Schering AG ZK-230211; and Zeneca
ZD-182780.
[0179] Preferred hormonal agents that may be used in the present
invention include, but are not limited to, those identified in
Table No. 5, below.
9TABLE NO. 5 Hormonal agents Common Name/ Compound Trade Name
Company Reference Dosage 2-methoxyestradiol EntreMed; EntreMed 2-ME
N-(S)-tetrahydrofuroyl- A-84861 Abbott Gly-D2Nal-D4ClPhe-D3Pal-
Ser-NMeTyr-DLys(Nic)-Leu- Lys(Isp)-Pro-DAla-NH2 raloxifene
[3R-1-(2,2-Dimethoxyethyl)-3-((4- AG-041R Chugai WO 94/19322
methylphenyl)aminocarbonylmethyl)-3-(N'-
(4-methylphenyl)ureido)-indoline-2-one] AN-207 Asta WO 97/19954
Medica Ethanamine,2-[4-(4-chloro-1,2-diphenyl-1- toremifene; Orion
EP 95875 60 mg/d butenyl)phenoxy]-N,N-dimethyl-,- (Z)- FARESTON
.RTM. Pharma Ethanamine,2-[4-(1,2-diphenyl-1- tamoxifen Zeneca U.S.
Pat. No. 4536516 For butenyl)phenoxy]-N,N-di- methyl-,(Z)-
NOLVADEX(R) patients with breast cancer, the recommended daily dose
is 20-40 mg. Dosages greater than 20 mg per day should be divided
(morning and evening). D-Alaninamide N-acetyl-3-(2- Antide; Ares-
WO 89/01944 25 or naphthalenyl)-D-alanyl-4-chloro- ORF-23541 Serono
50 microg/ D-phenylalanyl-3-(3-pyridinyl)-D- kg sc
alanyl-L-seryl-N6-(3-py- ridinylcarbonyl)-
L-lysyl-N6-(3-pyridinylcarbonyl)-
D-lysyl-L-leucyl-N6-(1-methylethyl)-L- lysyl-L-prolyl- B2036-
Sensus PEG; Somaver; Trovert 4-Methyl-2-[4-[2-(1- EM-800; Laval
piperidinyl)ethoxy]phenyl]-7- EM-652 University
(pivaloyloxy)-3-[4-(pivaloyloxy)phenyl]- 2H-1-benzopyran letrozol
U.S. Pat. No. 4749346 goserelin U.S. Pat. No. 4100274
3-[4-[1,2-Diphenyl-1(Z)- GW-5638 Glaxo
butenyl]phenyl]-2(E)-propenoic acid Wellcome
Estra-1,3,5(10)-triene-3,17- ICI- Zeneca EP 34/6014 250 mg/mth
diol,7-[9-[(4,4,5,5,5- 182780; pentafluoro-pentyl)sulfinyl]-
Faslodex; nonyl]-,(7alpha,17beta)- ZD-182780 J015X Tulane
University LG-1127; Ligand LG-1447 Pharma- ceuticals LG-2293 Ligand
Pharma- ceuticals LG-2527; Ligand LG-2716 Pharma- ceuticals
buserelin, Peptech Peptech; deslorelin, Peptech; PTL-03001;
triptorelin, Peptech LR-103 Bone Care International
[2-(4-Hydroxyphenyl)-6-hydroxynap- hthalen- LY-326315 Lilly WO
9609039 1-yl] [4-[2- (1-piperdinyl)ethoxy]phenyl]methane
hydrochloride LY- Lilly 353381- HCl LY-326391 Lilly LY-353381 Lilly
LY-357489 Lilly MPV- Orion EP 476944 0.3-300 mg 2213ad Pharma
Isobutyryl-Tyr-D-Arg-Asp-Ala- MZ-4-71 Tulane
Ile-(4-Cl)-Phe-Thr-Asn-Ser-Tyr- University
Arg-Lys-Val-Leu-(2-aminobutyryl)- Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-
Gln-Asp-Ile-Nle-Ser 4-guanidinobutylamide
Androst-4-ene-3,6,17-trione,14-hydroxy- NKS01; Snow EP 300062
14alpha- Brand OHAT; 14OHAT 3beta,16beta,17alpha-trihydroxycholest-
OSW-1 5-en-22-one-16-O-(2-0-4-methoxybenzoyl-
beta-D-xylopyranosyl)-(1-3- )(2-0-acetyl-
alpha-L-arabinopyranoside) Spiro [estra-4,9-diene-17,2'(3'H)- Org-
Akzo EP 289073 furan]-3-one,11-[4- 31710; Nobel
(dimethylamino)phenyl]- Org-31806 4',5'-dihydro-6-methyl-,
(6beta,11beta,17beta)- (22RS)-N-(1,1,1-trifluoro-2- PNU- Pharmacia
phenylprop-2-yl)-3-oxo-4-aza- 156765; & Upjohn
5alpha-androst-1-ene-17beta-carboxamide FCE-28260
1-[(benzofuran-2yl)-4- Menarini chlorophenylmethyl]imidazole
Tryptamine derivatives Rhone- WO 96/35686 Poulenc Rorer Permanently
ionic derivatives of Pharmos WO 95/26720 steroid hormones and their
antagonists Novel tetrahydronaphthofuranone Meiji WO 97/30040
derivatives Seika SMT-487; Novartis 90Y- octreo- tide
D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2 TT-232 2-(1H-imidazol-4-ylmeth-
yl)-9H- YM-116 Yamanouchi carbazole monohydrochloride monohydrate
4-[N-(4-bromobenzyl)-N-(4- YM-511 Yamanouchi
cyanophenyl)amino]-4H-1,2,4-triazole 2-(1H-imidazol-4-ylmethyl)-9H-
- YM-55208; Yamanouchi carbazole monohydrochloride monohydrate
YM-53789 ZK-1911703 Schering AG ZK-230211 Schering AG abarelix
Praecis Pharma- ceuticals Androsta-5,16-dien-3-ol,17- abiraterone
BTG (3-pyridinyl)-,acetate(ester),(3beta)- acetate; CB-7598;
CB-7630 2,6-Piperidinedione,3-(4- aminoglutethimide; Novartis U.S.
Pat. No. 3944671 aminophenyl)-3-ethyl- Ciba- 16038; Cytadren;
Elimina; Orimeten; Orimetene; Orimetine
1,3-Benzenediacetonitrile,alpha,alpha,alpha',alpha'- anastrozole;
Zeneca EP 296749 1 mg/day tetramethyl-5-(1H-1,2,4-tri-
azol-1-ylmethyl)- Arimidex; ICI-D1033; ZD-1033
5-Oxo-L-prolyl-L-histidyl-L-tryptophyl-L- avorelin; Medi- EP 23904
seryl-L-tyrosyl-2-methyl-D-tryptophyl-L- Meterelin olanum
leucyl-L-arginyl-N-ethyl-L-prolinamide Propanamide,N-[4-cyano-3-
bicalutamide; Zeneca EP 100172 (trifluoromethyl)phenyl]-3-[(4-
Casodex; fluorophenyl)sulfonyl]-2-hydroxy-2- Cosudex;
methyl-,(+/-)- ICI-176334 Luteinizing hormone- buserelin; Hoechst
GB 15/23623 200-600 releasing factor (pig),6-[O- Hoe-766; Marion
microg/day (1,1-dimethylethyl)-D-serine]-9-(N- Profact; Roussel
ethyl-L-prolinamide)-10-deglycinamide- Receptal; S-746766;
Suprecor; Suprecur; Suprefact; Suprefakt
D-Alaninamide,N-acetyl-3-(2-naphthalenyl)- cetrorelix; Asta EP
29/9402 D-alanyl-4-chloro-D-phenylalanyl- SB-075; Medica
3-(3-pyridinyl)-D-alanyl-L- SB-75 seryl-L-tyrosyl-N5-(aminocarbony-
l)- D-ol-L-leucyl-L-arginyl-L-prolyl- Phosphonic
acid,(dichloromethylene) clodronate Schering bis-,disodium salt-
disodium, AG Leiras; Bonefos; Clastoban; KCO-692 Luteinizing
hormone- deslorelin; Roberts U.S. Pat. No. 4034082 releasing factor
(pig),6-D- gonadorelin tryptophan-9-(N-ethyl-L- analogue,
prolinamide)-10-deglycinamide- Roberts; LHRH analogue, Roberts;
Somagard Phenol,3-[1-[4- droloxifene; Klinge EP 54168
[2-(dimethylamino)ethoxy]phenyl]-2- FK-435;
phenyl-1-butenyl]-,(E)-[CA S] K-060; K-21060E; RP 60850
4-Azaandrost-1-ene-17- dutasteride; Glaxo carboxamide,N-(2,5-
GG-745; Wellcome bis(trifluoromethyl) phenyl)-3- GI-198745
oxo-,(5alpha,17beta)- Androstan-17-ol,2,3-epithio-, epitiostanol;
Shionogi U.S. Pat. No. 3230215 (2alpha,3alpha,5alpha,17beta)-
10275-S; epithioan drostanol; S-10275; Thiobrestin; Thiodrol
Androsta-3,5-diene-3- epristeride; Smith- EP 289327 0.4-160
carboxylic acid,17-(((1,1- ONO-9302; Kline mg/day
dimethylethyl)amino)carbonyl)-(17beta)- SK&F-105657; Beecham
SKB-105657 estrone 3-O-sulfamate estrone 3-O- sulfamate
19-Norpregna-1,3,5(10)-trien- ethinyl Schering DE 1949095
20-yne-3,17-diol,3-(2- estradiol AG propanesulfonate),(17alpha)-
sulfonate; J96; Turisteron Androsta-1,4-diene-3,17- exemestane;
Pharmacia DE 3622841 5 mg/kg dione,6-methylene- FCE-24304 &
Upjohn Benzonitrile,4-(5,6,7,8- fadrozole; Novartis EP 165904 1 mg
po bid tetrahydroimidazo[1,5-a]- pyridin- Afema;
5-yl)-,monohydrochloride Arensin; CGS-16949; CGS-16949A; CGS-20287;
fadrozole monohydro- chloride 4-Azaandrost-1-ene-17- finasteride;
Merck & Co EP 155096 5 mg/day
carboxamide,N-(1,1-dimethylethyl)- Andozac; 3-oxo-,(5alpha,17beta)-
ChibroPro scar; Finastid; MK-0906; MK-906; Procure; Prodel;
Propecia; Proscar; Proskar; Prostide; YM-152
Propanamide,2-methyl-N-[4- flutamide; Schering U.S. Pat. No.
4329364 nitro-3-(trifluoromethyl)phenyl]- Drogenil; Plough Euflex;
Eulexin; Eulexine; Flucinom; Flutamida; Fugerel; NK-601; Odyne;
Prostogenat; Sch- 13521 Androst-4-ene-3,17-dione,4-hydroxy-
formestane; Novartis EP 346953 250 or 4-HAD; 600 mg/day 4-OHA; po
CGP-32349; CRC-82/01; Depot; Lentaron
[N-Ac-D-Nal,D-pCl-Phe,D-Pal,D- ganirelix; Roche EP 312052
hArg(Et)2,hArg(Et)2,D-Ala]GnRH- Org-37462; RS-26306 gonadorelin
Shire agonist, Shire Luteinizing hormone- goserelin; Zeneca U.S.
Pat. No. 4100274 releasing factor (pig),6-[O- ICI-
(1,1-dimethylethyl)-D-serine]-10- 118630;
deglycinamide-,2-(aminocarbonyl)hydrazide Zoladex; Zoladex LA hCG;
Milkhaus gonadotrophin; LDI-200 human NIH chorionic gonadotrophin;
hCG Pyrrolidine,1-[2-[4-[1-(4- idoxifene; BTG EP 260066
iodophenyl)-2-phenyl-1- CB-7386; butenyl]phenoxy]ethyl]-,(E)-
CB-7432; SB-223030 isocordoin Indena 2,4(1H,3H)-Quinazolinedione,3-
ketanserin; Johnson & EP 13612 [2-[4-(4-fluorobenzoyl)-
Aseranox; Johnson 1-piperidinyl]ethyl]- Ketensin; KJK-945;
ketanserine; Perketan; R-41468; Serefrex; Serepress; Sufrexal;
Taseron L-Threoninamide,3-(2-naphthalenyl)-D- lanreotide; Beaufour-
EP 215171 alanyl-L-cysteinyl-L-tyrosyl-D- Angiopeptin; Ipsen
tryptophyl-L-lysyl-L-valyl-L- BIM-23014; cysteinyl-,cyclic
(2-7)-disulfide Dermopeptin; Ipstyl; Somatuline; Somatuline LP
Benzonitrile,4,4'-(1H-1,2,4- letrozole; Novartis EP 236940 2.5
mg/day triazol-1-ylmethylene)bis- - CGS-20267; Femara Luteinizing
hormone- leuprolide, Atrix releasing factor (pig),6-D- Atrigel;
leucine-9-(N-ethyl-L-prolinamide)- leuprolide, 10-deglycinamide-
Atrix Luteinizing hormone- leuprorelin; Abbott U.S. Pat. No.
4005063 3.75 microg releasing factor (pig),6-D- Abbott- sc q 28
leucine-9-(N-ethyl-L-prolinamide)-10- 43818; days deglycinamide-
Carcinil; Enantone; Leuplin; Lucrin; Lupron; Lupron Depot;
leuprolide, Abbott; leuprolide, Takeda; leuprorelin, Takeda;
Procren Depot; Procrin; Prostap; Prostap SR; TAP-144-SR Luteinizing
hormone- leuprorelin, Alza releasing factor (pig),6-D- DUROS;
leucine-9-(N-ethyl-L-prolinamide)- leuprolide, 10-deglycinamide-
DUROS; leuprorelin 1H-Benzimidazole,5-[(3- liarozole; Johnson &
EP 260744 300 mg bid chlorophenyl)-1H-imidazol-1- Liazal; Johnson
ylmethyl]- Liazol; liarozole fumarate; R-75251; R-85246; Ro-85264
Urea,N'-[(8alpha)-9,10- lisuride VUFB didehydro-6-methylergolin-8-
hydrogen yl]-N,N-diethyl-,(Z)-2- maleate; butenedioate(1:1)
Cuvalit; Dopergin; Dopergine; Eunal; Lysenyl; Lysenyl Forte;
Revanil Pentanoic acid,4-[(3,4- loxiglumide; Rotta WO 87/03869
dichlorobenzoyl)amino]-5-[(3- CR-1505 Research
methoxypropyl)pentylamino]-5- oxo-,(+/-)-
Androstane,2,3-epithio-17-[(1- mepitiostane; Shionogi U.S. Pat. No.
3567713 methoxycyclopentyl)oxy]-, S-10364;
(2alpha,3alpha,5alpha,17beta)- Thioderon Phenol,4-[1-[4-
miproxifene Taiho WO 87/07609 20 mg/day [2-(dimethylamino)ethoxy]p-
henyl]-2 - phosphate; [4-(1-methylethyl)phenyl]-1- DP-TAT-59;
butenyl]-,dihydrogen phosphate(ester),(E)- TAT-59 Luteinizing
hormone- nafarelin; Roche EP 21/234 releasing factor (pig),
6-[3-(2- NAG, naphthalenyl)-D-alanine]- Syntex; Nasanyl; RS-94991;
RS-94991- 298; Synarel; Synarela; Synrelina 2,4-Imidazolidinedione,
nilutamide; Hoechst U.S. Pat. No. 4472382
5,5-dimethyl-3-[4-nitro-3- Anandron; Marion
(trifluoromethyl)phenyl]- Nilandron; Roussel Notostran; RU-23908
obesity Lilly WO 96/24670 gene; diabetes gene; leptin
L-Cysteinamide,D-phenylalanyl- octreotide; Novartis EP 29/579
L-cysteinyl-L-phenylalanyl-D- Longastatina; tryptophyl-L-lysyl-L-
octreotide threonyl-N-[2-hydroxy-1- pamoate;
(hydroxymethyl)propyl]-,cyclic(2-7)- Sandostatin;
disulfide,[R-(R*,R*)]- Sandostatin LAR; Sandostatina; Sandostatine;
SMS-201-995 Pyrrolidine,1-[2-(p-(7- ormeloxifene; Central DE
2329201 methoxy-2,2-dimethyl-3-phenyl- 6720-CDRI; Drug
4-chromanyl)phenoxy)ethyl]-,trans- Centron; Research Choice-7;
Inst. centchroman; Saheli 2-Oxapregna-4,6-diene-3,20-dione,17-
osaterone Teikoku EP 193871 (acetyloxy)-6-chloro- acetate; Hormone
Hipros; TZP-4238 Pregn-4-ene-3,20-dione progesterone; Columbia
Crinone Laboratories Sulfamide,N,N-diethyl-N'- quinagolide;
Novartis EP 77754 (1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-
CV-205-502; 1-propylbenzo[g]quinolin-3-yl)-, Norprolac;
(3alpha,4aalpha,10abeta)-(+/-)- SDZ-205-502
L-Proline,1-(N2-(N-(N-(N-(N- ramorelix; Hoechst EP 451791
(N-(N-(N-acetyl-3-(2- Hoe-013; Marion naphthalenyl)-D-alanyl)-4-ch-
loro-D- Hoe-013C; Roussel phenylalanyl)-D-tryptophyl)-L- Hoe-2013
seryl)-L-tyrosyl)-O-(6-deoxy-alpha-L- mannopyranosyl)-D-seryl-
)-L-leucyl)-L- arginyl)-,2-(aminocarbonyl)hydrazide- somatostatin
Tulane analogues University Ethanamine,2-[4-(1,2-diphenyl-1-
tamoxifen; Zeneca U.S. Pat. No. 4536516
butenyl)phenoxy]-N,N-dimethyl-,(Z)- Ceadan; ICI-46474; Kessar;
Nolgen; Nolvadex; Tafoxen; Tamofen; Tamoplex; Tamoxasta; Tamoxen;
Tomaxen tamoxifen Pharmos methiodide Ethanamine,2-[4-(1,2-
tamoxifen Douglas diphenyl-1-butenyl)phenoxy- ]- N,N-dimethyl-,(z)-
D-Alaninamide,N-acetyl-3-(2- teverelix; Asta
naphthalenyl)-D-alanyl-4-chloro- Antarelix Medica D-pheny
lalanyl-3-(3-pyridinyl)- D-alanyl-L-seryl-L-tyrosyl- -N6-
(aminocarbonyl)-D-lysyl-L-leucyl-
N6-(1-methylethyl)-L-lysyl-L-prolyl- Ethanamine,2-[4-(4-chloro-
toremifene; Orion EP 95875 60 mg po 1,2-diphenyl-1-butenyl)phenoxy-
]- Estrimex; Pharma N,N-dimethyl-,(Z)- Fareston; FC-1157; FC-1157a;
NK-622 Luteinizing hormone- triptorelin; Debio- U.S. Pat. No.
4010125 releasing factor (pig), ARVEKAP; pharm 6-D-tryptophan-
AY-25650; BIM-21003; BN-52104; Decapeptyl; WY-42422
L-Tryptophanamide,D-phenylalanyl-L-cysteinyl-L- vapreotide; Debio-
EP 203031 500 microg tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-
BMY-41606; pharm sc tid cysteinyl-,cyclic (2-7)-disulfide-
Octastatin; RC-160 1H-Benzotriazole,6-[(4- vorozole; Johnson &
EP 293978 2.5 mg/day chlorophenyl)-1H-1,2,4-triazol-1- R-76713;
Johnson ylmethyl]-1-methyl- R-83842; Rivizor
[0180] A sixth family of antineoplastic agents which may be used in
combination with the present invention consists of a miscellaneous
family of antineoplastic agents including, but not limited to
alpha-carotene, alpha-difluoromethyl-arginine, acitretin, Biotec
AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine,
Angiostat, ankinomycin, anti-neoplaston A10, antineoplaston A2,
antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel
APD, aphidicolin glycinate, asparaginase, Avarol, baccharin,
batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015,
bisantrene, Bristo-Myers BMY-40481, Vestar boron-10,
bromofosfamide, Wellcome BW-502, Wellcome BW-773, calcium
carbonate, Calcet, Calci-Chew, Calci-Mix, Roxane calcium carbonate
tablets, caracemide, carmethizole hydrochloride, Ajinomoto CDAF,
chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,
Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert
CI-941, Warner-Lambert CI-958, clanfenur, claviridenone, ICN
compound 1259, ICN compound 4711, Contracan, Cell Pathways CP-461,
Yakult Honsha CPT-11, crisnatol, curaderm, cytochalasin B,
cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine,
datelliptinium, DFMO, didemnin-B, dihaematoporphyrin ether,
dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, Toyo
Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel, Encore
Pharmaceuticals E7869, elliprabin, elliptinium acetate, Tsumura
EPMTC, ergotamine, etoposide, etretinate, Eulexinr, Cell Pathways
Exisulind.RTM. (sulindac sulphone or CP-246), fenretinide, Merck
Research Labs Finasteride, Florical, Fujisawa FR-57704, gallium
nitrate, gemcitabine, genkwadaphnin, Gerimed, Chugai GLA-43, Glaxo
GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross
HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosine,
irinotecan, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477,
ketoconazole, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp
KI-8110, American Cyanamid L-623, leucovorin, levamisole,
leukoregulin, lonidamine, Lundbeck LU-23-112, Lilly LY-186641,
Materna, NCI (US) MAP, marycin, Merrel Dow MDL-27048, Medco
MEDR-340, megestrol, merbarone, merocyanine derivatives,
methylanilinoacridine, Molecular Genetics MGI-136, minactivin,
mitonafide, mitoquidone, Monocal, mopidamol, motretinide, Zenyaku
Kogyo MST-16, Mylanta, N-(retinoyl)amino acids, Nilandron; Nisshin
Flour Milling N-021, N-acylated-dehydroalanines, nafazatrom, Taisho
NCU-190, Nephro-Calci tablets, nocodazole derivative, Normosang,
NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580,
octreotide, Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel,
pancratistatin, pazelliptine, Warner-Lambert PD-111707,
Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre
PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin,
polypreic acid, Efamol porphyrin, probimane, procarbazine,
proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane,
retinoids, Encore Pharmaceuticals R-flurbiprofen, Sandostatin;
Sapporo Breweries RBS, restrictin-P, retelliptine, retinoic acid,
Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, Scherring-Plough
SC-57050, Scherring-Plough SC-57068, selenium(selenite and
selenomethionine), SmithKline SK&F-104864, Sumitomo SM-108,
Kuraray SMANCS, SeaPharm SP-10094, spatol, spirocyclopropane
derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554,
strypoldinone, Stypoldione, Suntory SUN 0237, Suntory SUN 2071,
Sugen SU-101, Sugen SU-5416, Sugen SU-6668, sulindac, sulindac
sulfone; superoxide dismutase, Toyama T-506, Toyama T-680, taxol,
Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak TJB-29,
tocotrienol, Topostin, Teijin TT-82, Kyowa Hakko UCN-01, Kyowa
Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastine sulfate,
vincristine, vindesine, vinestramide, vinorelbine, vintriptol,
vinzolidine, withanolides, Yamanouchi YM-534, Zileuton,
ursodeoxycholic acid, and Zanosar.
[0181] Preferred miscellaneous agents that may be used in the
present invention include, but are not limited to, those identified
in Table No. 6, below.
10TABLE NO. 6 Miscellaneous agents Common Name/ Compound Trade Name
Company Reference Dosage Flutamide; 2-methyl-N-(4-nitro-3- EULEXIN
.RTM. Schering 750 mg/d in (trifluoro-methyl)phenyl)propanamide
Corp 3 8-hr doses. Ketoconazole U.S. Pat. No. 4144346 leucovorin
U.S. Pat. No. 4148999 irinotecan U.S. Pat. No. 4604463 levamisole
GB 11/20406 megestrol U.S. Pat. No. 4696949 paclitaxel U.S. Pat.
No. 5641803 Nilutamide 5,5-dimethyl Nilandron Hoechst A total
3-(4-nitro 3-(trifluoromethyl)phenyl)2,- 4- Marion daily dose
imidazolidinedione Roussel of 300 mg for 30 days followed
thereafter by three tablets (50 mg each) once a day for a total
daily dosage of 150 mg. Vinorelbine EP 0010458 vinblastine
vincristine Octreotide acetate L- Sandostatin Sandoz s.c. or i.v.
cysteinamide, D-phenylalanyl- Pharma- administration
L-cysteinyl-L-phenylalanyl- ceuticals Acromegaly:
D-tryptophyl-L-lysyl-L- 50-300 threonyl-NSAIDs-(2- mcgm tid.
hydroxy-1-(hydroxymethyl)propyl)-, Carcinoid cyclic-disulfide; (R-
tumors: (R*,R*) acetate salt 100-600 mcgm/d (mean = 300 mcgm/d)
Vipomas: 200-300 mcgm in first two weeks of therapy Streptozocin
Zanosar Pharmacia i.v. 1000 Streptozocin 2-deoxy-2- & Upjohn
mg/M2 of (((methylnitrosamino)carbonyl)amino)- body alpha(and
beta)-D-glucopyranose) surface per week for two weeks. topotecan
U.S. Pat. No. 5004758 Selenium EP 804927 L-selenomethionine ACES
.RTM. J.R. Carlson Labora- tories calcium carbonate sulindac
sulfone Exisuland .RTM. U.S. Pat. No. 5858694 ursodeoxycholic acid
U.S. Pat. No. 5843929 Cell Pathways CP-461
[0182] Some additional preferred antineoplastic agents include
those described in the individual patents listed in Table No. 7
below, and are hereby individually incorporated by reference.
11TABLE NO. 7 Antineoplastic agents EP 0296749 EP 0882734 EP
00253738 GB 02/135425 WO 09/832762 EP 0236940 U.S. Pat. No. 5338732
U.S. Pat. No. 4418068 U.S. Pat. No. 4692434 U.S. Pat. No. 5464826
U.S. Pat. No. 5061793 EP 0702961 EP 0702961 EP 0702962 EP 0095875
EP 0010458 EP 0321122 U.S. Pat. No. 5041424 JP 60019790 WO
09/512606 U.S. Pat. No. 4,808614 U.S. Pat. No. 4526988 CA 2128644
U.S. Pat. No. 5455270 WO 99/25344 WO 96/27014 U.S. Pat. No. 5695966
DE 19547958 WO 95/16693 WO 82/03395 U.S. Pat. No. 5789000 U.S. Pat.
No. 5902610 EP 189990 U.S. Pat. No. 4500711 FR 24/74032 U.S. Pat.
No. 5925699 WO 99/25344 U.S. Pat. No. 4537883 U.S. Pat. No. 4808614
U.S. Pat. No. 5464826 U.S. Pat. No. 5366734 U.S. Pat. No. 4767628
U.S. Pat. No. 4100274 U.S. Pat. No. 4584305 U.S. Pat. No. 4336381
JP 5050383 JP 5050384 JP 5064281 JP 51146482 JP 5384981 U.S. Pat.
No. 5472949 U.S. Pat. No. 5455270 U.S. Pat. No. 4140704 U.S. Pat.
No. 4537883 U.S. Pat. No. 4814470 U.S. Pat. No. 3590028 U.S. Pat.
No. 4564675 U.S. Pat. No. 4526988 U.S. Pat. No. 4100274 U.S. Pat.
No. 4604463 U.S. Pat. No. 4144346 U.S. Pat. No. 4749713 U.S. Pat.
No. 4148999 GB 11/20406 U.S. Pat. No. 4696949 U.S. Pat. No. 4310666
U.S. Pat. No. 5641803 U.S. Pat. No. 4418068 U.S. Pat. No. 5,004758
EP 0095875 EP 0010458 U.S. Pat. No. 4935437 U.S. Pat. No. 4,278689
U.S. Pat. No. 4820738 U.S. Pat. No. 4413141 U.S. Pat. No. 5843917
U.S. Pat. No. 5,858694 U.S. Pat. No. 4330559 U.S. Pat. No. 5851537
U.S. Pat. No. 4499072 U.S. Pat. No. 5,217886 WO 98/25603 WO
98/14188
[0183] Table No. 8 provides illustrative examples of median dosages
for selected cancer agents that may be used in combination with an
antiangiogenic agent. It should be noted that specific dose regimen
for the chemotherapeutic agents below depends upon dosing
considerations based upon a variety of factors including the type
of neoplasia; the stage of the neoplasm; the age, weight, sex, and
medical condition of the patient; the route of administration; the
renal and hepatic function of the patient; and the particular
combination employed.
12TABLE NO. 8 Median dosages for selected cancer agents. NAME OF
CHEMOTHERAPEUTIC AGENT MEDIAN DOSAGE Asparaginase 10,000 units
Bleomycin Sulfate 15 units Carboplatin 50-450 mg. Carmustine 100
mg. Cisplatin 10-50 mg. Cladribine 10 mg. Cyclophosphamide 100 mg.-
(lyophilized) 2 gm. Cyclophosphamide (non- 100 mg.- lyophilized) 2
gm. Cytarabine (lyophilized 100 mg.- powder) 2 gm. Dacarbazine 100
mg.- 200 mg. Dactinomycin 0.5 mg. Daunorubicin 20 mg.
Diethylstilbestrol 250 mg. Doxorubicin 10-150 mg. Etidronate 300
mg. Etoposide 100 mg. Floxuridine 500 mg. Fludarabine Phosphate 50
mg. Fluorouracil 500 mg.- 5 gm. Goserelin 3.6 mg. Granisetron
Hydrochloride 1 mg. Idarubicin 5-10 mg. Ifosfamide 1-3 gm.
Leucovorin Calcium 50-350 mg. Leuprolide 3.75-7.5 rng.
Mechlorethamine 10 mg. Medroxyprogesterone 1 gm. Melphalan 50 gm.
Methotrexate 20 mg.- 1 gm. Mitomycin 5-40 mg. Mitoxantrone 20-30
mg. Ondansetron Hydrochloride 40 mg. Paclitaxel 30 mg. Pamidronate
Disodium 30-90 mg. Pegaspargase 750 units Plicamycin 2,500 mcgm.
Streptozocin 1 gm. Thiotepa 15 mg. Teniposide 50 mg. Vinblastine 10
mg. Vincristine 1-5 mg. Aldesleukin 22 million units Epoetin Alfa
2,000-10,000 units Filgrastim 300-480 mcgm. Immune Globulin 500
mg.- 10 gm. Interferon Alpha-2a 3-36 million units Interferon
Alpha-2b 3-50 million units Levamisole 50 mg. Octreotide
1,000-5,000 mcgm. Sargramostim 250-500 mcgm.
[0184] The anastrozole used in the therapeutic combinations of the
present invention can be prepared in the manner set forth in U.S.
Pat. No. 4,935,437. The capecitabine used in the therapeutic
combinations of the present invention can be prepared in the manner
set forth in U.S. Pat. No. 5,472,949. The carboplatin used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in U.S. Pat. No. 5,455,270. The Cisplatin
used in the therapeutic combinations of the present invention can
be prepared in the manner set forth in U.S. Pat. No. 4,140,704. The
cyclophoshpamide used in the therapeutic combinations of the
present invention can be prepared in the manner set forth in U.S.
Pat. No. 4,537,883. The eflornithine (DFMO) used in the therapeutic
combinations of the present invention can be prepared in the manner
set forth in U.S. Pat. No. 4,413,141. The docetaxel used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in U.S. Pat. No. 4,814,470. The doxorubicin
used in the therapeutic combinations of the present invention can
be prepared in the manner set forth in U.S. Pat. No. 3,590,028. The
etoposide used in the therapeutic combinations of the present
invention can be prepared in the manner set forth in U.S. Pat. No.
4,564,675. The fluorouricil used in the therapeutic combinations of
the present invention can be prepared in the manner set forth in
U.S. Pat. No. 4,336,381. The gemcitabine used in the therapeutic
combinations of the present invention can be prepared in the manner
set forth in U.S. Pat. No. 4,526,988. The goserelin used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in U.S. Pat. No. 4,100,274. The irinotecan
used in the therapeutic combinations of the present invention can
be prepared in the manner set forth in U.S. Pat. No. 4,604,463. The
ketoconazole used in the therapeutic combinations of the present
invention can be prepared in the manner set forth in U.S. Pat. No.
4,144,346. The letrozole used in the therapeutic combinations of
the present invention can be prepared in the manner set forth in
U.S. Pat. No. 4,749,713. The leucovorin used in the therapeutic
combinations of the present invention can be prepared in the manner
set forth in U.S. Pat. No. 4,148,999. The levamisole used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in GB 11/20,406. The megestrol used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in U.S. Pat. No. 4,696,949. The
mitoxantrone used in the therapeutic combinations of the present
invention can be prepared in the manner set forth in U.S. Pat. No.
4,310,666. The paclitaxel used in the therapeutic combinations of
the present invention can be prepared in the manner set forth in
U.S. Pat. No. 5,641,803. The Retinoic acid used in the therapeutic
combinations of the present invention can be prepared in the manner
set forth in U.S. Pat. No. 4,843,096. The tamoxifen used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in U.S. Pat. No. 4,418,068. The topotecan
used in the therapeutic combinations of the present invention can
be prepared in the manner set forth in U.S. Pat. No. 5,004,758. The
toremifene used in the therapeutic combinations of the present
invention can be prepared in the manner set forth in EP 00/095,875.
The vinorelbine used in the therapeutic combinations of the present
invention can be prepared in the manner set forth in EP 00/010,458.
The sulindac sulfone used in the therapeutic combinations of the
present invention can be prepared in the manner set forth in U.S.
Pat. No. 5,858,694. The selenium (selenomethionine) used in the
therapeutic combinations of the present invention can be prepared
in the manner set forth in EP 08/04,927. The ursodeoxycholic acid
used in the therapeutic combinations of the present invention can
be prepared in the manner set forth in WO 97/34,608.
Ursodeoxycholic acid can also be prepared according to the manner
set forth in EP 05/99,282. Finally, ursodeoxycholic acid can be
prepared according to the manner set forth in U.S. Pat. No.
5,843,929.
[0185] Still more preferred antineoplastic agents include:
anastrozole, calcium carbonate, capecitabine, carboplatin,
cisplatin, Cell Pathways CP-461, cyclophosphamide, docetaxel,
doxorubicin, etoposide, Exisulind.RTM., fluorouracil (5-FU),
fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole,
letrozol, leucovorin, levamisole, megestrol, mitoxantrone,
paclitaxel, raloxifene, retinoic acid, tamoxifen, thiotepa,
topotecan, toremifene, vinorelbine, vinblastine, vincristine,
selenium (selenomethionine), ursodeoxycholic acid, sulindac sulfone
and eflornithine (DFMO).
[0186] The phrase "taxane" includes a family of diterpene alkaloids
all of which contain a particular eight (8) member "taxane" ring
structure. Taxanes such as paclitaxel prevent the normal post
division breakdown of microtubules which form to pull and separate
the newly duplicated chromosome pairs to opposite poles of the cell
prior to cell division. In cancer cells which are rapidly dividing,
taxane therapy causes the microtubules to accumulate which
ultimately prevents further division of the cancer cell. Taxane
therapy also affects other cell processes dependant on microtubules
such as cell motility, cell shape and intracellular transport. The
major adverse side-effects associated with taxane therapy can be
classified into cardiac effects, neurotoxicity, haematological
toxicity, and hypersensitivity reactions. (See Exp. Opin. Thera.
Patents (1998) 8(5), hereby incorporated by reference). Specific
adverse side-effects include neutropenia, alopecia, bradycardia,
cardiac conduction defects, acute hypersensitivity reactions,
neuropathy, mucositis, dermatitis, extravascular fluid
accumulation, arthralgias, and myalgias. Various treatment regimens
have been developed in an effort to minimize the side effects of
taxane therapy, but adverse side-effects remain the limiting factor
in taxane therapy.
[0187] Taxane derivatives have been found to be useful in treating
refractory ovarian carcinoma, urothelial cancer, breast carcinoma,
melanoma, non-small-cell lung carcinoma, gastric, and colon
carcinomas, squamous carcinoma of the head and neck, lymphoblastic,
myeloblastic leukemia, and carcinoma of the esophagus.
[0188] Paclitaxel is typically administered in a 15-420 mg/m.sup.2
dose over a 6 to 24 hour infusion. For renal cell carcinoma,
squamous carcinoma of head and neck, carcinoma of esophagus, small
and non-small cell lung cancer, and breast cancer, paclitaxel is
typically administered as a 250 mg/m.sup.2 24 hour infusion every 3
weeks. For refractory ovarian cancer paclitaxel is typically dose
escalated starting at 110 mg/m.sup.2.
[0189] Docetaxel is typically administered in a 60-100 mg/M.sup.2
i.v. over 1 hour, every three weeks. It should be noted, however,
that specific dose regimen depends upon dosing considerations based
upon a variety of factors including the type of neoplasia; the
stage of the neoplasm; the age, weight, sex, and medical condition
of the patient; the route of administration; the renal and hepatic
function of the patient; and the particular agents and combination
employed.
[0190] In one embodiment, paclitaxel is used in the present
invention in combination with an integrin antagonist and with
cisplatin, cyclophosphamide, or doxorubicin for the treatment of
breast cancer. In another embodiment paciltaxel is used in
combination with an integrin antagonist, cisplatin or carboplatin,
and ifosfamide for the treatment of ovarian cancer.
[0191] In another embodiment docetaxal is used in the present
invention in combination with an integrin antagonist and in
combination with cisplatin, cyclophosphamide, or doxorubicin for
the treatment of ovary and breast cancer and for patients with
locally advanced or metastatic breast cancer who have progressed
during anthracycline based therapy.
[0192] The following references listed in Table No. 9 below, hereby
individually incorporated by reference herein, describe various
taxanes and taxane derivatives suitable for use in the present
invention, and processes for their manufacture.
13TABLE NO. 9 Taxanes and taxane derivatives EP 694539 EP 683232 EP
639577 EP 627418 EP 604910 EP 797988 EP 727492 EP 767786 EP 767376
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WO 93/21173 EP 681574 EP 681575 EP 568203 EP 642503 EP 667772 EP
668762 EP 679082 EP 681573 EP 688212 EP 690712 EP 690853 EP 710223
EP 534708 EP 534709 EP 605638 EP 669918 EP 855909 EP 605638 EP
428376 EP 428376 EP 534707 EP 605637 EP 679156 EP 689436 EP 690867
EP 605637 EP 690867 EP 687260 EP 690711 EP 400971 EP 690711 EP
400971 EP 690711 EP 884314 EP 568203 EP 534706 EP 428376 EP 534707
EP 400971 EP 669918 EP 605637 U.S. Pat. No. 5015744 U.S. Pat. No.
5175315 U.S. Pat. No. 5243045 U.S. Pat. No. 5283253 U.S. Pat. No.
5250683 U.S. Pat. No. 5254703 U.S. Pat. No. 5274124 U.S. Pat. No.
5284864 U.S. Pat. No. 5284865 U.S. Pat. No. 5350866 U.S. Pat. No.
5227400 U.S. Pat. No. 5229526 U.S. Pat. No. 4876399 U.S. Pat. No.
5136060 U.S. Pat. No. 5336785 U.S. Pat. No. 5710287 U.S. Pat. No.
5714513 U.S. Pat. No. 5717115 U.S. Pat. No. 5721268 U.S. Pat. No.
5723634 U.S. Pat. No. 5728725 U.S. Pat. No. 5728850 U.S. Pat. No.
5739362 U.S. Pat. No. 5760219 U.S. Pat. No. 5760252 U.S. Pat. No.
5384399 U.S. Pat. No. 5399726 U.S. Pat. No. 5405972 U.S. Pat. No.
5430160 U.S. Pat. No. 5466834 U.S. Pat. No. 5489601 U.S. Pat. No.
5532363 U.S. Pat. No. 5539103 U.S. Pat. No. 5574156 U.S. Pat. No.
5587489 U.S. Pat. No. 5618952 U.S. Pat. No. 5637732 U.S. Pat. No.
5654447 U.S. Pat. No. 4942184 U.S. Pat. No. 5059699 U.S. Pat. No.
5157149 U.S. Pat. No. 5202488 U.S. Pat. No. 5750736 U.S. Pat. No.
5202488 U.S. Pat. No. 5549830 U.S. Pat. No. 5281727 U.S. Pat. No.
5019504 U.S. Pat. No. 4857653 U.S. Pat. No. 4924011 U.S. Pat. No.
5733388 U.S. Pat. No. 5696153 WO 93/06093 WO 93/06094 WO 94/10996
WO 9/10997 WO 94/11362 WO 94/15599 WO 94/15929 WO 94/17050 WO
94/17051 WO 94/17052 WO 94/20088 WO 94/20485 WO 94/21250 WO
94/21251 WO 94/21252 WO 94/21623 WO 94/21651 WO 95/03265 WO
97/09979 WO 97/42181 WO 99/08986 WO 99/09021 WO 93/06079 U.S. Pat.
No. 5202448 U.S. Pat. No. 5019504 U.S. Pat. No. 4857653 U.S. Pat.
No. 4924011 WO 97/15571 WO 96/38138 U.S. Pat. No. 5489589 EP 781778
WO 96/11683 EP 639577 EP 747385 U.S. Pat. No. 5422364 WO 95/11020
EP 747372 WO 96/36622 U.S. Pat. No. 5599820 WO 97/10234 WO 96/21658
WO 97/23472 U.S. Pat. No. 5550261 WO 95/20582 WO 97/28156 WO
96/14309 WO 97/32587 WO 96/28435 WO 96/03394 WO 95/25728 WO
94/29288 WO 96/00724 WO 95/02400 EP 694539 WO 95/24402 WO 93/10121
WO 97/19086 WO 97/20835 WO 96/14745 WO 96/36335
[0193] U.S. Pat. No. 5,019,504 describes the isolation of
paclitaxel and related alkaloids from culture grown Taxus
brevifolia cells.
[0194] U.S. Pat. No. 5,675,025 describes methods for synthesis of
Taxol.RTM., Taxol.RTM. analogues and intermediates from baccatin
III.
[0195] U.S. Pat. No. 5,688,977 describes the synthesis of Docetaxel
from 10-deacetyl baccatin III.
[0196] U.S. Pat. No. 5,202,488 describes the conversion of
partially purified taxane mixture to baccatin III.
[0197] U.S. Pat. No. 5,869,680 describes the process of preparing
taxane derivatives.
[0198] U.S. Pat. No. 5,856,532 describes the process of the
production of Taxol.RTM..
[0199] U.S. Pat. No. 5,750,737 describes the method for paclitaxel
synthesis.
[0200] U.S. Pat. No. 6,688,977 describes methods for docetaxel
synthesis.
[0201] U.S. Pat. No. 5,677,462 describes the process of preparing
taxane derivatives.
[0202] U.S. Pat. No. 5,594,157 describes the process of making
Taxol.RTM. derivatives.
[0203] Some preferred taxanes and taxane derivatives are described
in the patents listed in Table No. 10 below, and are hereby
individually incorporated by reference herein.
14TABLE NO. 10 Some preferred taxanes and taxane derivatives U.S.
Pat. No. 5015744 U.S. Pat. No. 5136060 U.S. Pat. No. 5175315 U.S.
Pat. No. 5200534 U.S. Pat. No. 5194635 U.S. Pat. No. 5227400 U.S.
Pat. No. 4924012 U.S. Pat. No. 5641803 U.S. Pat. No. 5059699 U.S.
Pat. No. 5157049 U.S. Pat. No. 4942184 U.S. Pat. No. 4960790 U.S.
Pat. No. 5202488 U.S. Pat. No. 5675025 U.S. Pat. No. 5688977 U.S.
Pat. No. 5750736 U.S. Pat. No. 5684175 U.S. Pat. No. 5019504 U.S.
Pat. No. 4814470 WO 95/01969
[0204] The phrase "retinoid" includes compounds which are natural
and synthetic analogues of retinol (Vitamin A). The retinoids bind
to one or more retinoic acid receptors to initiate diverse
processes such as reproduction, development, bone formation,
cellular proliferation and differentiation, apoptosis,
hematopoiesis, immune function and vision. Retinoids are required
to maintain normal differentiation and proliferation of almost all
cells and have been shown to reverse/suppress carcinogenesis in a
variety of in vitro and in vivo experimental models of cancer, see
(Moon et al., Ch. 14 Retinoids and cancer. In The Retinoids, Vol.
2. Academic Press, Inc. 1984). Also see Roberts et al. Cellular
biology and biochemistry of the retinoids. In The Retinoids, Vol.
2. Academic Press, Inc. 1984, hereby incorporated by reference),
which also shows that vesanoid (tretinoid trans retinoic acid) is
indicated for induction of remission in patients with acute
promyelocytic leukemia (APL).
[0205] A synthetic description of retinoid compounds, hereby
incorporated by reference, is described in: Dawson M I and Hobbs P
D. The synthetic chemistry of retinoids: in The retinoids, 2.sup.nd
edition. M B Sporn, A B Roberts, and D S Goodman(eds). New York:
Raven Press, 1994, pp 5-178.
[0206] Lingen et al. describe the use of retinoic acid and
interferon alpha against head and neck squamous cell carcinoma
(Lingen, M W et al., Retinoic acid and interferon alpha act
synergistically as antiangiogenic and antitumor agents against
human head and neck squamous cell carcinoma. Cancer Research 58
(23) 5551-5558 (1998), hereby incorporated by reference).
[0207] Iurlaro et al. describe the use of beta interferon and
13-cis retinoic acid to inhibit angiogenesis. (Iurlaro, M et al.,
Beta interferon inhibits HIV-1 Tat-induced angiogenesis: synergism
with 13-cis retinoic acid. European Journal of Cancer 34 (4)
570-576 (1998), hereby incorporated by reference).
[0208] Majewski et al. describe Vitamin D3 and retinoids in the
inhibition of tumor cell-induced angiogenesis. (Majewski, S et al.,
Vitamin D3 is a potent inhibitor of tumor cell-induced
angiogenesis. J. Invest. Dermatology. Symposium Proceedings, 1 (1),
97-101 (1996), hereby incorporated by reference.
[0209] Majewski et al. describe the role of retinoids and other
factors in tumor angiogenesis. Majewski, S et al., Role of
cytokines, retinoids and other factors in tumor angiogenesis.
Central-European journal of Immunology 21 (4) 281-289 (1996),
hereby incorporated by reference).
[0210] Bollag describes retinoids and alpha-interferon in the
prevention and treatment of neoplastic disease. (Bollag W.
Retinoids and alpha-interferon in the prevention and treatment of
preneoplastic and neoplastic diseases. Chemotherapie Journal,
(Suppl) 5 (10) 55-64 (1996), hereby incorporated by reference.
[0211] Bigg, H F et al. describe all-trans retinoic acid with basic
fibroblast growth factor and epidermal growth factor to stimulate
tissue inhibitor of metalloproteinases from fibroblasts. (Bigg, HF
et al., All-trans-retoic acid interacts synergystically with basic
fibroblast growth factor and epidermal growth factor to stimulate
the production of tissue inhibitor of metalloproteinases from
fibroblasts. Arch. Biochem. Biophys. 319 (1) 74-83 (1995), hereby
incorporated by reference).
[0212] Nonlimiting examples of retinoids that may be used in the
present invention are identified in Table No. 11 below.
15TABLE NO. 11 Retinoids Common Name/Trade Compound Name Company
Reference Dosage CD-271 Adapaline EP 199636 Tretinoin Vesanoid
Roche 45 transretinoic acid Holdings mg/M.sup.2/day as two evenly
divided doses until complete remission 2,4,6,8- etretinate Roche
U.S. Pat. No. 4215215 .25-1.5 Nonatetraenoic acid, isoetretin;
Holdings mg/kg/day 9-(4-methoxy-2,3,6- Ro-10-9359;
trimethylphenyl)-3,7- Ro-13-7652; dimethyl-, ethyl Tegison; ester,
(all-E)- Tigason Retinoic acid, 13-cis- isotretinoin Roche U.S.
Pat. No. 4843096 .5 to 2 Accutane; Holdings mg/kg/day Isotrex;
Ro-4-3780; Roaccutan; Roaccutane Roche Ro- Roche 40-0655 Holdings
Roche Ro- Roche 25-6760 Holdings Roche Ro- Roche 25-9022 Holdings
Roche Ro- Roche 25-9716 Holdings Benzoic acid,4-[[3,5- TAC-101
Taiho bis(trimethylsilyl)benzoyl] amino]- Pharmaceutical
Retinamide, N-(4-hydroxyphenyl)- fenretinide 50-400 4-HPR;
mg/kg/day HPR; McN-R-1967 (2E,4E,6E)-7-(3,5-Di-tert- LGD-1550
Ligand 20 butylphenyl)-3-methylocta- ALRT-1550; Pharmaceuticas;
microg/m2/ 2,4,6-trienoic acid ALRT-550; Allergan day to LG-1550
U.S. Pat. No.A 400 microg/m2/ day administered as a single daily
oral dose Molecular U.S. Pat. No. 4885311 Design MDI-101 Molecular
U.S. Pat. No. 4677120 Design MDI-403 Benzoic acid,4-(1-(5,6,7,8-
bexarotene WO 94/15901 tetrahydro-3,5,5,8,8- LG-1064;
pentamethyl-2- LG-1069; naphthalenyl)ethenyl)- LGD-1069; Targretin;
Targretin Oral; Targretin Topical Gel Benzoic acid,4-(1-(5,6,7,8-
bexarotene, R P tetrahydro-3,5,8,8- soft gel Scherer pentamethyl-2-
bexarotene, naphthalenyl)ethenyl)- Ligand; bexaroten
(2E,4E)-3-methyl-5- WO 96/05165 [3-(5,5,8,8-tetramethyl-
5,6,7,8-tetrahydro-naphthalen- 2-yl)-thiopen-2-yl]-penta-
2,4-dienoic acid SR-11262F Hoffmann- La Roche Ltd BMS-181162
Bristol EP 476682 Myers Squibb N-(4-hydroxyphenyl)retinamide IIT
Research Cancer Institute Research 39, 1339-1346 (1979) AGN-193174
Allergan WO 96/33716 U.S. Pat. No.A
[0213] The following individual patent references listed in Table
No. 12 below, hereby individually incorporated by reference,
describe various retinoid and retinoid derivatives suitable for use
in the present invention described herein, and processes for their
manufacture.
16TABLE NO. 12 Retinoids U.S. Pat. No. 4215215 U.S. Pat. No.
4885311 U.S. Pat. No. 4677120 U.S. Pat. No. 4105681 U.S. Pat. No.
5260059 U.S. Pat. No. 4503035 U.S. Pat. No. 5827836 U.S. Pat. No.
3878202 U.S. Pat. No. 4843096 WO 96/05165 WO 97/34869 WO 97/49704
EP 19/9636 WO 96/33716 WO 97/24116 WO 97/09297 WO 98/36742 WO
97/25969 WO 96/11686 WO 94/15901 WO 97/24116 CH 61/6134 DE 2854354
EP 579915 U.S. Pat. No. 5547947 EP 552624 EP 728742 EP 331983 EP
476682
[0214] Some preferred retinoids include Accutane; Adapalene;
Allergan AGN-193174; Allergan AGN-193676; Allergan AGN-193836;
Allergan AGN-193109; Aronex AR-623; BMS-181162; Galderma CD-437;
Eisai ER-34617; Etrinate; Fenretinide; Ligand LGD-1550;
lexacalcitol; Maxia Pharmaceuticals MX-781; mofarotene; Molecular
Design MDI-101; Molecular Design MDI-301; Molecular Design MDI-403;
Motretinide; Eisai
4-(2-[5-(4-methyl-7-ethylbenzofuran-2-yl)pyrrolyl]) benzoic acid;
Johnson & Johnson
N-[4-[2-thyl-1-(1H-imidazol-1-yl)butyl]phenyl]-2-benzothiazolam-
ine; Soriatane; Roche SR-11262; Tocoretinate; Advanced Polymer
Systems trans-retinoic acid; UAB Research Foundation UAB-8;
Tazorac; TopiCare; Taiho TAC-101; and Vesanoid.
[0215] cGMP phosphodiesterase inhibitors, including Sulindac
sulfone (Exisuland.RTM.) and CP-461 for example, are apoptosis
inducers and do not inhibit the cyclooxygenase pathways. cGMP
phosphodiesterase inhibitors increase apoptosis in tumor cells
without arresting the normal cycle of cell division or altering the
cell's expression of the p53 gene.
[0216] Ornithine decarboxylase is a key enzyme in the polyamine
synthesis pathway that is elevated in most tumors and premalignant
lesions. Induction of cell growth and proliferation is associated
with dramatic increases in ornithine decarboxylase activity and
subsequent polyamine synthesis. Further, blocking the formation of
polyamines slows or arrests growth in transformed cells.
Consequently, polyamines are thought to play a role in tumor
growth. Difluoromethylornithine (DFMO) is a potent inhibitor of
ornithine decarboxylase that has been shown to inhibit
carcinogen-induced cancer development in a variety of rodent models
(Meyskens et al. Development of Difluoromethylornithine (DFMO) as a
chemoprevention agent. Clin. Cancer Res. 1999 May, 5(%):945-951,
hereby incorporated by reference, herein). DFMO is also known as
2-difluoromethyl-2,5-diaminopentanoic acid, or
2-difluoromethyl-2,5-diami- novaleric acid, or a-(difluoromethyl)
ornithine; DFMO is marketed under the tradename Elfornithine.RTM..
Therefore, the use of DFMO in combination with COX-2 inhibitors is
contemplated to treat or prevent cancer, including but not limited
to colon cancer or colonic polyps.
[0217] Populations with high levels of dietary calcium have been
reported to be protected from colon cancer. In vivo, calcium
carbonate has been shown to inhibit colon cancer via a mechanism of
action independent from COX-2 inhibition. Further, calcium
carbonate is well tolerated. A combination therapy including an
integrin antagonist, calcium carbonate and a selective COX-2
inhibitor is contemplated to treat or prevent cancer, including but
not limited to colon cancer or colonic polyps.
[0218] Several studies have focused attention on bile acids as a
potential mediator of the dietary influence on colorectal cancer
risk. Bile acids are important detergents for fat solubilization
and digestion in the proximal intestine. Specific transprot
processes in the apical domain of the terminal ileal enterocyte and
basolateral domain of the hepatocyte account for the efficient
conservation in the enterohepatic circulation. Only a small
fraction of bile acids enter the colon; however, perturbations of
the cycling rate of bile acids by diet (e.g. fat) or surgery
may-increase the fecal bile load and perhaps account for the
associated increased risk of colon cancer. (Hill M J, Bile flow and
colon cancer. 238 Mutation Review, 313 (1990). Ursodeoxycholate
(URSO), the hydrophilic 7-beta epimer of chenodeoxycholate, is non
cytotoxic in a variety of cell model systems including colonic
epithelia. URSO is also virtually free of side effects. URSO, at
doses of 15 mg/kg/day used primarily in biliary cirrhosis trials
were extremely well tolerated and without toxicity. (Pourpon et
al., A multicenter, controlled trial of ursodiol for the treatment
of primary biliary cirrhosis. 324 New Engl. J. Med. 1548 (1991)).
While the precise mechanism of URSO action is unknown, beneficial
effects of URSO therapy are related to the enrichment of the
hepatic bile acid pool with this hydrophilic bile acid. It has thus
been hypothesized that bile acids more hydrophilic than URSO will
have even greater beneficial effects than URSO. For example,
tauroursodeoxycholate (TURSO) the taurine conjugate of URSO.
Non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit the
neoplastic transformation of colorectal epithelium. The likely
mechanism to explain this chemopreventive effect is inhibition of
prostaglandin synthesis. NSAIDs inhibit cyclooxygenase, the enzyme
that converts arachidonic acid to prostaglandins and thromboxanes.
However, the potential chemopreventive benefits of NSAIDs such as
sulindac or mesalamine are tempered by their well known toxicities
and moderately high risk of intolerance. Abdominal pain, dispepsia,
nausea, diarrhea, constipation, rash, dizziness, or headaches have
been reported in up to 9% of patients. The elderly appear to be
particularly vulnerable as the incidence of NSAID-induced
gastroduodenal ulcer disease, including gastrointestinal bleeding,
is higher in those over the age of 60; this is also the age group
most likely to develop colon cancer, and therefore most likely to
benefit from chemoprevention. The gastrointestinal side effects
associated with NSAID use result from the inhibition of
cyclooxygenase-1, an enzyme responsible for maintenance of the
gastric mucosa. Therefore, the use of COX-2 inhibitors in
combination with URSO is contemplated to treat or prevent cancer,
including but not limited to colon cancer or colonic polyps; it is
contemplated that this treatment will result in lower
gastrointestinal side effects than the combination of standard
NSAIDs and URSO.
[0219] An additional class of antineoplastic agents that may be
used in the present invention include nonsteroidal antiinflammatory
drugs (NSAIDs). NSAIDs have been found to prevent the production of
prostaglandins by inhibiting enzymes in the human arachidonic
acid/prostaglandin pathway, including the enzyme cyclooxygenase
(COX). However, for the purposes of the present invention the
definition of an NSAID does not include the "cyclooxygenase-2
inhibitors" described herein. Thus the phrase "nonsteroidal
antiinflammatory drug" or "NSAID" includes agents that specifically
inhibit cyclooxygenase-1, without significant inhibition of
cyclooxygenase-2; or inhibit cyclooxygenase-1 and cyclooxygenase-2
at substantially the same potency; or inhibit neither
cyclooxygenase-1 or cyclooxygenase-2. The potency and selectivity
for the enzyme cyclooxygenase-1 and cyclooxygenase-2 can be
determined by assays well known in the art, see for example,
Cromlish and Kennedy, Biochemical Pharmacology, Vol. 52, pp
1777-1785, 1996.
[0220] Examples of NSAIDs that can be used in the combinations of
the present invention include sulindac, indomethacin, naproxen,
diclofenac, tolectin, fenoprofen, phenylbutazone, piroxicam,
ibuprofen, ketophen, mefenamic acid, tolmetin, flufenamic acid,
nimesulide, niflumic acid, piroxicam, tenoxicam, phenylbutazone,
fenclofenac, flurbiprofen, ketoprofen, fenoprofen, acetaminophen,
salicylate and aspirin.
[0221] The term "clinical tumor" includes neoplasms that are
identifiable through clinical screening or diagnostic procedures
including, but not limited to, palpation, biopsy, cell
proliferation index, endoscopy, mammagraphy, digital mammography,
ultrasonography, computed tomagraphy (CT), magnetic resonance
imaging (MRI), positron emmission tomaagraphy (PET), radiography,
radionuclide evaluation, CT- or MRI-guided aspiration cytology, and
imaging-guided needle biopsy, among others. Such diagnostic
techniques are well known to those skilled in the art and are
described in Cancer Medicine 4.sup.th Edition, Volume One. J. F.
Holland, R. C. Bast, D. L. Morton, E. Frei III, D. W. Kufe, and R.
R. Weichselbaum (Editors). Williams & Wilkins, Baltimore
(1997).
[0222] The term "tumor marker" or "tumor biomarker" encompasses a
wide variety of molecules with divergent characteristics that
appear in body fluids or tissue in association with a clinical
tumor and also includes tumor-associated chromosomal changes. Tumor
markers fall primarily into three categories: molecular or cellular
markers, chromosomal markers, and serological or serum markers.
Molecular and chromosomal markers complement standard parameters
used to describe a tumor (i.e. histopathology, grade, tumor size)
and are used primarily in refining disease diagnosis and prognosis
after clinical manifestation. Serum markers can often be measured
many months before clinical tumor detection and are thus useful as
an early diagnostic test, in patient monitoring, and in therapy
evaluation.
[0223] Molecular Tumor Markers
[0224] Molecular markers of cancer are products of cancer cells or
molecular changes that take place in cells because of activation of
cell division or inhibition of apoptosis. Expression of these
markers can predict a cell's malignant potential. Because cellular
markers are not secreted, tumor tissue samples are generally
required for their detection. Non-limiting examples of molecular
tumor markers that can be used in the present invention are listed
in Table No. 1, below.
17TABLE NO. 1 Non-limiting Examples of Molecular Tumor Markers
Tumor Marker Breast p53 Breast, Ovarian ErbB-2/Her-2 Breast S phase
and ploidy Breast pS2 Breast MDR2 Breast urokinase plasminogen
activator Breast, Colon, Lung myc family
[0225] Chromosomal Tumor Markers
[0226] Somatic mutations and chromosomal aberrations have been
associated with a variety of tumors. Since the identification of
the Philadelphia Chromosome by Nowel and Hungerford, a wide effort
to identify tumor-specific chromosomal alterations has ensued.
Chromosomal cancer markers, like cellular markers, are can be used
in the diagnosis and prognosis of cancer. In addition to the
diagnostic and prognostic implications of chromosomal alterations,
it is hypothesized that germ-line mutations can be used to predict
the likelihood that a particular person will develop a given type
of tumor. Non-limiting examples of chromosomal tumor markers that
can be used in the present invention are listed in Table No. 2,
below.
18TABLE NO. 2 Non-limiting Examples of Chromosomal Tumor Markers
Tumor Marker Breast 1p36 loss Breast 6q24-27 loss Breast 11q22-23
loss Breast 11q13 amplification Breast TP53 mutation Colon Gain of
chromosome 13 Colon Deletion of short arm of chromosome 1 Lung Loss
of 3p Lung Loss of 13q Lung Loss of 17p Lung Loss of 9p
[0227] Serological Tumor Markers
[0228] Serum markers including soluble antigens, enzymes and
hormones comprise a third category of tumor markers. Monitoring
serum tumor marker concentrations during therapy provides an early
indication of tumor recurrence and of therapy efficacy. Serum
markers are advantageous for patient surveillance compared to
chromosomal and cellular markers because serum samples are more
easily obtainable than tissue samples, and because serum assays can
be performed serially and more rapidly. Serum tumor markers can be
used to determine appropriate therapeutic doses within individual
patients. For example, the efficacy of a combination regimen
consisting of chemotherapeutic and antiangiogenic agents can be
measured by monitoring the relevant serum cancer marker levels.
Moreover, an efficacious therapy dose can be achieved by modulating
the therapeutic dose so as to keep the particular serum tumor
marker concentration stable or within the reference range, which
may vary depending upon the indication. The amount of therapy can
then be modulated specifically for each patient so as to minimize
side effects while still maintaining stable, reference range tumor
marker levels. Table No. 3 provides non-limiting examples of
serological tumor markers that can be used in the present
invention.
19TABLE NO. 3 Non-limiting Examples of Serum Tumor Markers Cancer
Type Marker Germ Cell Tumors a-fetoprotein (AFP) Germ Cell Tumors
human chorionic gonadotrophin (hCG) Germ Cell Tumors placental
alkaline phosphatase (PLAP) Germ Cell Tumors lactate dehydrogenase
(LDH) Prostate prostate specific antigen (PSA) Breast
carcinoembryonic antigen (CEA) Breast MUC-1 antigen (CA15-3) Breast
tissue polypeptide antigen (TPA) Breast tissue polypeptide specific
antigen (TPS) Breast CYFRA 21.1 Breast soluble erb-B-2 Ovarian
CA125 Ovarian OVX1 Ovarian cancer antigen CA72-4 Ovarian TPA
Ovarian TPS Gastrointestinal CD44v6 Gastrointestinal CEA
Gastrointestinal cancer antigen CA19-9 Gastrointestinal NCC-ST-439
antigen (Dukes C) Gastrointestinal cancer antigen CA242
Gastrointestinal soluble erb-B-2 Gastrointestinal cancer antigen
CA195 Gastrointestinal TPA Gastrointestinal YKL-40 Gastrointestinal
TPS Esophageal CYFRA 21-1 Esophageal TPA Esophageal TPS Esophageal
cancer antigen CA19-9 Gastric Cancer CEA Gastric Cancer cancer
antigen CA19-9 Gastric Cancer cancer antigen CA72-4 Lung neruon
specific enolase (NSE) Lung CEA .backslash.Lung CYFRA 21-1 Lung
cancer antigen CA 125 Lung TPA Lung squamous cell carcinoma antigen
(SCC) Pancreatic cancer ca19-9 Pancreatic cancer ca50 Pancreatic
cancer ca119 Pancreatic cancer ca125 Pancreatic cancer CEA
Pancreatic cancer Renal Cancer CD44v6 Renal Cancer E-cadherin Renal
Cancer PCNA (proliferating cell nuclear antigen)
EXAMPLES
[0229] Germ Cell Cancers
[0230] Non-limiting examples of tumor markers useful in the present
invention for the detection of germ cell cancers include, but are
not limited to, a-fetoprotein (AFP), human chorionic gonadotrophin
(hCG) and its beta subunit (hCGb), lactate dehydrogenase (LDH), and
placental alkaline phosphatase (PLAP).
[0231] AFP has an upper reference limit of approximately -10 kU/L
after the first year of life and may be elevated in germ cell
tumors, hepatocellular carcinoma and also in gastric, colon,
biliary, pancreatic and lung cancers. AFP serum half life is
approximately five days after orchidectomy. According to EGTM
recommendations, AFP serum levels less than 1,000 kU/L correlate
with a good prognosis, AFP levels between 1,000 and 10,000 kU/L,
inclusive, correlate with intermediate prognosis, and AFP levels
greater than 10,000 U/L correlate with a poor prognosis.
[0232] HCG is synthesized in the placenta and is also produced by
malignant cells. Serum hCG concentrations may be increased in
pancreatic adenocarcinomas, islet cell tumors, tumors of the small
and large bowel, hepatoma, stomach, lung, ovaries, breast and
kidney. Because some tumors only hCGb, measurement of both hCG and
hCGb is recommended. Normally, serum hCG in men and pre-menopausal
women is as high as -5 U/L while post-menopausal women have levels
up to -10 U/L. Serum half life of hCG ranges from 16-24 hours.
According to the EGTM, hCG serum levels under 5000 U/L correlate
with a good prognosis, levels between 5000 and 50000 U/L,
inclusively correlate with an intermediate prognosis, and hCG serum
levels greater than 50000 U/L correlate with a poor prognosis.
Further, normal hCG half lives correlate with good prognosis while
prolonged half lives correlate with poor prognosis.
[0233] LDH is an enzyme expressed in cardiac and skeletal muscle as
well as in other organs. The LDH-1 isoenzyme is most commonly found
in testicular germ cell tumors but can also occur in a variety of
benign conditions such as skeletal muscle disease and myocardial
infarction. Total LDH is used to measure independent prognostic
value in patients with advanced germ cell tumors. LDH levels less
than 1.5.times. the reference range are associated with a good
prognosis, levels between 1.5 and 10.times. the reference range,
inclusive, are associated with an intermediate prognosis, and
levels more than 10.times.the reference range are associated with a
poor prognosis.
[0234] PLAP is a enzyme of alkaline phosphatase normally expressed
by placental syncytiotrophoblasts. Elevated serum concentrations of
PLAP are found in seminomas, non-seminomatous tumors, and ovarian
tumors, and may also provide a marker for testicular tumors. PLAP
has a normal half life after surgical resection of between 0.6 and
2.8 days.
[0235] Prostate Cancer
[0236] A nonlimiting example of a tumor marker useful in the
present invention for the detection of prostate cancer is prostate
specific antigen (PSA). PSA is a glycoprotein that is almost
exclusively produced in the prostate. In human serum, uncomplexed
f-PSA and a complex of f-PSA with al-anthichymotrypsin make up
total PSA (t-PSA). T-PSA is useful in determining prognosis in
patients that are not currently undergoing anti-androgen treatment.
Rising t-PSA levels via serial measurement indicate the presence of
residual disease.
[0237] Breast Cancer
[0238] Non-limiting examples of serum tumor markers useful in the
present invention for the detection of breast cancer include, but
is not limited to carcinoembryonic antigen (CEA) and MUC-1 (CA
15.3). Serum CEA and CA15.3 levels are elevated in patients with
node involvement compared to patients without node involvement, and
in patients with larger tumors compared to smaller tumors. Normal
range cutoff points (upper limit) are 5-10 mg/L for CEA and 35-60
u/ml for CA15.3. Additional specificity (99.3%) is gained by
confirming serum levels with two serial increases of more than
15%.
[0239] Ovarian Cancer
[0240] A non-limiting example of a tumor marker useful in the
present invention for the detection of ovarian cancer is CA125.
Normally, women have serum CA125 levels between 0-35 kU/L; 99% of
post-menopausal women have levels below 20 kU/L. Serum
concentration of CA125 after chemotherapy is a strong predictor of
outcome as elevated CA125 levels are found in roughly 80% of all
patients with epithelial ovarian cancer. Further, prolonged CA125
half-life or a less than 7-fold decrease during early treatment is
also a predictor of poor disease prognosis.
[0241] Gastrointestinal Cancers
[0242] A non-limiting example of a tumor marker useful in the
present invention for the detection of colon cancer is
carcinoembryonic antigen (CEA). CEA is a glycoprotein produced
during embryonal and fetal development and has a high sensitivity
for advanced carcinomas including those of the colon, breast,
stomach and lung. High pre- or postoperative concentrations
(>2.5 ng/ml) of CEA are associated with worse prognosis than are
low concentrations. Further, some studies in the literature report
that slow rising CEA levels indicates local recurrence while
rapidly increasing levels suggests hepatic metastasis.
[0243] Lung Cancer
[0244] Examples of serum markers useful in the present invention to
monitor lung cancer therapy include, but are not limited to, CEA,
cytokeratin 19 fragments (CYFRA 21-1), and Neuron Specific Enolase
(NSE).
[0245] NSE is a glycolytic isoenzyme of enolase produced in central
and peripheral neurons and malignant tumors of neuroectodermal
origin. At diagnosis, NSE concentrations greater than 25 ng/mL are
suggestive of malignancy and lung cancer while concentrations
greater than 100 ng/mL are suggestive of small cell lung
cancer.
[0246] CYFRA 21-1 is a tumor marker test which uses two specific
monoclonal antibodies against a cytokeratin 19 fragment. At
diagnosis, CYFRA 21-1 concentrations greater than 10 ng/mL are
suggestive of malignancy while concentrations greater than 30 ng/mL
are suggestive of lung cancer.
[0247] Accordingly, dosing of the integrin antagonist and
antineoplastic agent may be determined and adjusted based on
measurement of tumor markers in body fluids or tissues,
particularly based on tumor markers in serum. For example, a
decrease in serum marker level relative to baseline serum marker
prior to administration of the integrin antagonist and
antineoplastic agent indicates a decrease in cancer-associated
changes and provides a correlation with inhibition of the cancer.
In one embodiment, therefore, the method of the present invention
comprises administering the integrin antagonist and antineoplastic
agent at doses that in combination result in a decrease in one or
more tumor markers, particularly a decrease in one or more serum
tumor markers, in the mammal relative to baseline tumor marker
levels.
[0248] Similarly, decreasing tumor marker concentrations or serum
half lives after administration of the combination indicates a good
prognosis, while tumor marker concentrations which decline slowly
and do not reach the normal reference range predict residual tumor
and poor prognosis. Further, during follow-up therapy, increases in
tumor marker concentration predicts recurrent disease many months
before clinical manifestation.
[0249] In addition to the above examples, Table No. 4, below, lists
several references, hereby individually incorporated by reference
herein, that describe tumor markers and their use in detecting and
monitoring tumor growth and progression.
20TABLE NO. 4 Tumor marker references. European Group on Tumor
Markers Publications Committee. Consensus Recommendations.
Anticancer Research 19: 2785-2820 (1999) Human Cytogenetic Cancer
Markers. Sandra R. Wolman and Stewart Sell (eds.). Totowa, New
Jersey: Humana Press. 1997 Cellular Markers of Cancer. Carleton
Garrett and Stewart Sell (eds.). Totowa, New Jersey: Human Press.
1995
[0250] Also included in the combination of the invention are the
isomeric forms, prodrugs and tautomers of the described compounds
and the pharmaceutically-acceptable salts thereof. Illustrative
pharmaceutically acceptable salts are prepared from formic, acetic,
propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,
citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,
glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,
p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,
toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,
cyclohexylaminosulfonic, algenic, b-hydroxybutyric, galactaric and
galacturonic acids.
[0251] Suitable pharmaceutically-acceptable base addition salts of
compounds of the present invention include metallic ion salts and
organic ion salts. More preferred metallic ion salts include, but
are not limited to appropriate alkali metal (group Ia) salts,
alkaline earth metal (group IIa) salts and other physiological
acceptable metal ions. Such salts can be made from the ions of
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
Preferred organic salts can be made from tertiary amines and
quaternary ammonium salts, including in part, trimethylamine,
diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. All of the above salts can be
prepared by those skilled in the art by conventional means from the
corresponding compound of the present invention.
[0252] Administration Regimen
[0253] Any effective treatment regimen can be utilized and readily
determined and repeated as necessary to effect treatment. In
clinical practice, the compositions containing an integrin
antagonist alone or in combination with other therapeutic agents
are administered in specific cycles until a response is
obtained.
[0254] For patients who initially present without advanced or
metastatic cancer, an integrin antagonist in combination with
another integrin antagonist or one or more anticancer agents as an
immediate initial therapy prior to surgery, chemotherapy, or
radiation therapy, and as a continuous post-treatment therapy in
patients at risk for recurrence or metastasis (for example, in
adenocarcinoma of the prostate, risk for metastasis is based upon
high PSA, high Gleason's score, locally extensive disease, and/or
pathological evidence of tumor invasion in the surgical specimen).
The goal in these patients is to inhibit the growth of potentially
metastatic cells from the primary tumor during surgery or
radiotherapy and inhibit the growth of tumor cells from
undetectable residual primary tumor.
[0255] For patients who initially present with advanced or
metastatic cancer, an integrin antagonist in combination with
another integrin antagonist or one or more anticancer agents of the
present invention is used as a continuous supplement to, or
possible replacement for hormonal ablation. The goal in these
patients is to slow or prevent tumor cell growth from both the
untreated primary tumor and from the existing metastatic
lesions.
[0256] In addition, the invention may be particularly efficacious
during post-surgical recovery, where the present compositions and
methods may be particularly effective in lessening the chances of
recurrence of a tumor engendered by shed cells that cannot be
removed by surgical intervention.
[0257] Combinations With Other Treatments
[0258] Integrin antagonists may be used in conjunction with other
treatment modalities, including, but not limited to surgery and
radiation, hormonal therapy, chemotherapy, immunotherapy,
antiangiogenic therapy and cryotherapy. The present invention may
be used in conjunction with any current or future therapy.
[0259] The following discussion highlights some agents in this
respect, which are illustrative, not limitative. A wide variety of
other effective agents also may be used.
[0260] Surgery and Radiation
[0261] In general, surgery and radiation therapy are employed as
potentially curative therapies for patients under 70 years of age
who present with clinically localized disease and are expected to
live at least 10 years.
[0262] For example, approximately 70% of newly diagnosed prostate
cancer patients fall into this category. Approximately 90% of these
patients (65% of total patients) undergo surgery, while
approximately 10% of these patients (7% of total patients) undergo
radiation therapy. Histopathological examination of surgical
specimens reveals that approximately 63% of patients undergoing
surgery (40% of total patients) have locally extensive tumors or
regional (lymph node) metastasis that was undetected at initial
diagnosis. These patients are at a significantly greater risk of
recurrence. Approximately 40% of these patients will actually
develop recurrence within five years after surgery. Results after
radiation are even less encouraging. Approximately 80% of patients
who have undergone radiation as their primary therapy have disease
persistence or develop recurrence or metastasis within five years
after treatment. Currently, most of these surgical and radiotherapy
patients generally do not receive any immediate follow-up therapy.
Rather, for example, they are monitored frequently for elevated
Prostate Specific Antigen ("PSA"), which is the primary indicator
of recurrence or metastasis prostate cancer.
[0263] Thus, there is considerable opportunity to use the present
invention in conjunction with surgical intervention.
[0264] Hormonal Therapy
[0265] Hormonal ablation is the most effective palliative treatment
for the 10% of patients presenting with metastatic prostate cancer
at initial diagnosis. Hormonal ablation by medication and/or
orchiectomy is used to block hormones that support the further
growth and metastasis of prostate cancer. With time, both the
primary and metastatic tumors of virtually all of these patients
become hormone-independent and resistant to therapy. Approximately
50% of patients presenting with metastatic disease die within three
years after initial diagnosis, and 75% of such patients die within
five years after diagnosis. Continuous supplementation with
NAALADase inhibitor based drugs are used to prevent or reverse this
potentially metastasis-permissive state.
[0266] Among hormones which may be used in combination with the
present inventive compounds, diethylstilbestrol (DES), leuprolide,
flutamide, cyproterone acetate, ketoconazole and amino glutethimide
are preferred.
[0267] Immunotherapy
[0268] The integrin antagonists may also be used in combination
with monoclonal antibodies in treating cancer. For example
monoclonal antibodies may be used in treating prostate cancer. A
specific example of such an antibody includes cell
membrane-specific anti-prostate antibody.
[0269] The present invention may also be used with immunotherapies
based on polyclonal or monoclonal antibody-derived reagents, for
instance. Monoclonal antibody-based reagents are most preferred in
this regard. Such reagents are well known to persons of ordinary
skill in the art. Radiolabelled monoclonal antibodies for cancer
therapy, such as the recently approved use of monoclonal antibody
conjugated with strontium-89, also are well known to persons of
ordinary skill in the art.
[0270] Antiangiogenic Therapy
[0271] The MMP inhibitors may also be used in combianation with
other antiangiogenic agenst in treating cancer. Antiangiogenic
agents include but are not limited to Cox-2 inhibitors, integrin
antagonists, angiostatin, endostatin, thrombospondin-1, and
interferon alpha. Examples of preferred antiangiogenic agents
include, but are not limited to vitaxin, celecoxib, rofecoxib,
JTE-522, EMD-121974, and D-2163 (BMS-275291).
[0272] Cryotherapy
[0273] Cryotherapy recently has been applied to the treatment of
some cancers. Methods and compositions of the present invention
also could be used in conjunction with an effective therapy of this
type.
[0274] All of the various cell types of the body can be transformed
into benign or malignant neoplasia or tumor cells and are
contemplated as objects of the invention. A "benign" tumor cell
denotes the non-invasive and non-metastasized state of a neoplasm.
In man the most frequent neoplasia site is lung, followed by
colorectal, breast, prostate, bladder, pancreas, and then ovary.
Other prevalent types of cancer include leukemia, central nervous
system cancers, including brain cancer, melanoma, lymphoma,
erythroleukemia, uterine cancer, and head and neck cancer. Examples
1 through 9 are provided to illustrate contemplated therapeutic
combinations, and are not intended to limit the scope of the
invention.
Illustrations
[0275] The following non-limiting illustrative examples describe
various cancer diseases and therapeutic approaches that may be used
in the present invention, and are for illustrative purposes
only.
Example 1
[0276] Lung Cancer
[0277] In many countries including Japan, Europe and America, the
number of patients with lung cancer is fairly large and continues
to increase year after year and is the most frequent cause of
cancer death in both men and women. Although there are many
potential causes for lung cancer, tobacco use, and particularly
cigarette smoking, is the most important. Additionally, etiologic
factors such as exposure to asbestos, especially in smokers, or
radon are contributory factors. Also occupational hazards such as
exposure to uranium have been identified as an important factor.
Finally, genetic factors have also been identified as another
factor that increase the risk of cancer.
[0278] Lung cancers can be histologically classified into non-small
cell lung cancers (e.g. squamous cell carcinoma (epidermoid),
adenocarcinoma, large cell carcinoma (large cell anaplastic), etc.)
and small cell lung cancer (oat cell). Non-small cell lung cancer
(NSCLC) has different biological properties and responses to
chemotherapeutics from those of small cell lung cancer (SCLC).
Thus, chemotherapeutic formulas and radiation therapy are different
between these two types of lung cancer.
[0279] Non-Small Cell Lung Cancer
[0280] Where the location of the non-small cell lung cancer tumor
can be easily excised (stage I and II disease) surgery is the first
line of therapy and offers a relatively good chance for a cure.
However, in more advanced disease (stage IIIa and greater), where
the tumor has extended to tissue beyond the bronchopulmonary lymph
nodes, surgery may not lead to complete excision of the tumor. In
such cases, the patient's chance for a cure by surgery alone is
greatly diminished. Where surgery will not provide complete removal
of the NSCLC tumor, other types of therapies must be utilized.
[0281] Today radiation therapy is the standard treatment to control
unresectable or inoperable NSCLC. Improved results have been seen
when radiation therapy has been combined with chemotherapy, but
gains have been modest and the search continues for improved
methods of combining modalities.
[0282] Radiation therapy is based on the principle that high-dose
radiation delivered to a target area will result in the death of
reproductive cells in both tumor and normal tissues. The radiation
dosage regimen is generally defined in terms of radiation absorbed
dose (rad), time and fractionation, and must be carefully defined
by the oncologist. The amount of radiation a patient receives will
depend on various consideration but the two most important
considerations are the location of the tumor in relation to other
critical structures or organs of the body, and the extent to which
the tumor has spread. A preferred course of treatment for a patient
undergoing radiation therapy for NSCLC will be a treatment schedule
over a 5 to 6 week period, with a total dose of 50 to 60 Gy
administered to the patient in a single daily fraction of 1.8 to
2.0 Gy, 5 days a week. A Gy is an abbreviation for Gray and refers
to 100 rad of dose.
[0283] However, as NSCLC is a systemic disease, and radiation
therapy is a local modality, radiation therapy as a single line of
therapy is unlikely to provide a cure for NSCLC, at least for those
tumors that have metastasized distantly outside the zone of
treatment. Thus, the use of radiation therapy with other modality
regimens have important beneficial effects for the treatment of
NSCLC.
[0284] Generally, radiation therapy has been combined temporally
with chemotherapy to improve the outcome of treatment. There are
various terms to describe the temporal relationship of
administering radiation therapy in combination with integrin
antagonists and chemotherapy, and the following examples are the
preferred treatment regimens and are provided for illustration only
and are not intended to limit the use of other combinations.
"Sequential" therapy refers to the administration of chemotherapy
and/or integrin antagonists and/or radiation therapy separately in
time in order to allow the separate administration of either
chemotherapy and/or integrin antagonists, and/or radiation therapy.
"Concomitant" therapy refers to the administration of chemotherapy
and/or integrin antagonists, and/or radiation therapy on the same
day. Finally, "alternating therapy refers to the administration of
radiation therapy on the days in which chemotherapy and/or integrin
antagonist therapy would not have been administered if it was given
alone.
[0285] It is reported that advanced non-small cell lung cancers do
not respond favorably to single-agent chemotherapy and useful
therapies for advanced inoperable cancers have been limited.
(Journal of Clinical Oncology, vol. 10, pp. 829-838 (1992)).
[0286] Japanese Patent Kokai 5-163293 refers to some specified
antibiotics of 16-membered-ring macrolides as a drug delivery
carrier capable of transporting anthoracycline-type anticancer
drugs into the lungs for the treatment of lung cancers. However,
the macrolide antibiotics specified herein are disclosed to be only
a drug carrier, and there is no reference to the therapeutic use of
macrolides against non-small cell lung cancers.
[0287] WO 93/18,652 refers to the effectiveness of the specified
16-membered-ring macrolides such as bafilomycin, etc. in treating
non-small cell lung cancers, but they have not yet been clinically
practicable.
[0288] Pharmacology, vol. 41, pp. 177-183 (1990) describes that a
long-term use of erythromycin increases productions of interleukins
1, 2 and 4, all of which contribute to host immune responses, but
there is no reference to the effect of this drug on non-small cell
lung cancers.
[0289] Teratogenesis, Carcinogenesis, and Mutagenesis, vol. 10, pp.
477-501 (1990) describes that some of antimicrobial drugs can be
used as an anticancer agent, but does not refer to their
application to non-small cell lung cancers.
[0290] In addition, interleukins are known to have an antitumor
effect, but have not been reported to be effective against
non-small cell lung cancers.
[0291] Any 14- or 15-membered-ring macrolides have not been
reported to be effective against non-small cell lung cancers.
[0292] However, several chemotherapeutic agents have been shown to
be efficacious against NSCLC. Preferred chemotherapeutic agents
that can be used in the present invention against NSCLC include
etoposide, carboplatin, methotrexate, 5-Fluorouracil, epirubicin,
doxorubicin, taxol, inhibitor of normal mitotic activity; and
cyclophosphamide. Even more preferred chemotherapeutic agents
active against NSCLC include cisplatin, ifosfamide, mitomycin C,
epirubicin, vinblastine, and vindesine.
[0293] Other agents that are under investigation for use against
NSCLC include: camptothecins, a topoisomerase 1 inhibitor;
navelbine (vinorelbine), a microtubule assebly inhibitor;
gemcitabine, a deoxycytidine analogue; fotemustine, a nitrosourea
compound; and edatrexate, a antifol.
[0294] The overall and complete response rates for NSCLC has been
shown to increase with use of combination chemotherapy as compared
to single-agent treatment. Haskel C M: Chest. 99: 1325, 1991;
Bakowski M T: Cancer Treat Rev 10:159, 1983; Joss RA: Cancer Treat
Rev 11:205, 1984.
[0295] A preferred therapy for the treatment of NSCLC is a
combination of therapeutically effective amounts of an integrin
antagonist in combination with the following combinations of
antineoplastic agents: 1) itosfamide, cisplatin, etoposide; 2)
cyclophoshamide, doxorubicin, cisplatin; 3) isofamide, carboplatin,
etoposide; 4) bleomycin, etoposide, cisplatin; 5) isofamide,
mitomycin, cisplatin; 6) cisplatin, vinblastine; 7) cisplatin,
vindesine; 8) mitomycin C, vinblastine, cisplatin; 9) mitomycin C,
vindesine, cisplatin; 10) isofamide, etoposide; 11) etoposide,
cisplatin; 12) isofamide, mitomycin C; 13) flurouracil, cisplatin,
vinblastine; 14) carboplatin, etoposide; or radiation therapy.
[0296] Accordingly, apart from the conventional concept of
anticancer therapy, there is a strong need for the development of
therapies practicably effective for the treatment of non-small cell
lung cancers.
[0297] Small Cell Lung Cancer
[0298] Approximately 15 to 20 percent of all cases of lung cancer
reported worldwide is small cell lung cancer (SCLC). Ihde D C:
Cancer 54:2722, 1984. Currently, treatment of SCLC incorporates
multi-modal therapy, including chemotherapy, radiation therapy and
surgery. Response rates of localized or disseminated SCLC remain
high to systemic chemotherapy, however, persistence of the primary
tumor and persistence of the tumor in the associated lymph nodes
has led to the integration of several therapeutic modalities in the
treatment of SCLC.
[0299] A preferred therapy for the treatment of lung cancer is a
combination of therapeutically effective amounts of an integrin
antagonist in combination with the following antineoplastic agents:
vincristine, cisplatin, carboplatin, cyclophosphamide, epirubicin
(high dose), etoposide (VP-16) I.V., etoposide (VP-16) oral,
isofamide, teniposide (VM-26), and doxorubicin. Other preferred
single-agents chemotherapeutic agents that may be used in the
present invention include BCNU (carmustine), vindesine,
hexamethylmelamine (altretamine), methotrexate, nitrogen mustard,
and CCNU (lomustine). Other chemotherapeutic agents under
investigation that have shown activity againe SCLC include
iroplatin, gemcitabine, lonidamine, and taxol. Single-agent
chemotherapeutic agents that have not shown activity against SCLC
include mitoguazone, mitomycin C, aclarubicin, diaziquone,
bisantrene, cytarabine, idarubicin, mitomxantrone, vinblastine,
PCNU and esorubicin.
[0300] The poor results reported from single-agent chemotherapy has
led to use of combination chemotherapy.
[0301] A preferred therapy for the treatment of NSCLC is a
combination of therapeutically effective amounts of an integrin
antagonist in combination with the following combinations of
antineoplastic agents: 1) etoposide (VP-16), cisplatin; 2)
cyclophosphamide, adrianmycin [(doxorubicin), vincristine,
etoposide (VP-16)]; 3) Cyclophosphamide, adrianrycin(doxorubicin),
vincristine; 4) Etoposide (VP-16), ifosfamide, cisplatin; 5)
etoposide (VP-16), carboplatin; 6) cisplatin, vincristine
(Oncovin), doxorubicin, etoposide.
[0302] Additionally, radiation therapy in conjunction with the
preferred combinations of integrin antagonists and systemic
chemotherapy is contemplated to be effective at increasing the
response rate for SCLC patients. The typical dosage regimen for
radiation therapy ranges from 40 to 55 Gy, in 15 to 30 fractions, 3
to 7 times week. The tissue volume to be irradiated is determined
by several factors and generally the hilum and subcarnial nodes,
and bialteral mdiastinal nodes up to the thoraic inlet are treated,
as well as the primary tumor up to 1.5 to 2.0 cm of the
margins.
Example 2
[0303] Colorectal Cancer
[0304] Survival from colorectal cancer depends on the stage and
grade of the tumor, for example precursor adenomas to metastatic
adenocarcinoma. Generally, colorectal cancer can be treated by
surgically removing the tumor, but overall survival rates remain
between 45 and 60 percent. Colonic excision morbidity rates are
fairly low and is generally associated with the anastomosis and not
the extent of the removal of the tumor and local tissue. In
patients with a high risk of reoccurrence, however, chemotherapy
has been incorporated into the treatment regimen in order to
improve survival rates.
[0305] Tumor metastasis prior to surgery is generally believed to
be the cause of surgical intervention failure and up to one year of
chemotherapy is required to kill the non-excised tumor cells. As
severe toxicity is associated with the chemotherapeutic agents,
only patients at high risk of recurrence are placed on chemotherapy
following surgery. Thus, the incorporation of an antiangiogenesis
inhibitor into the management of colorectal cancer will play an
important role in the treatment of colorectal cancer and lead to
overall improved survival rates for patients diagnosed with
colorectal cancer.
[0306] A preferred combination therapy for the treatment of
colorectal cancer is surgery, followed by a regimen of one or more
chemotherapeutic agents and an integrin antagonist, cycled over a
one year time period. A more preferred combination therapy for the
treatment of colorectal cancer is a regimen of one or more integrin
antagonists, followed by surgical removal of the tumor from the
colon or rectum and then followed be a regimen of one or more
chemotherapeutic agents and one or more integrin antagonists,
cycled over a one year time period. An even more preferred therapy
for the treatment of colon cancer is a combination of
therapeutically effective amounts of one or more antiangiogenesis
agents including a matrix metalloproteinase inhibitor, a
cyclooxygenase-II inhibitor, or an integrin antagonist.
[0307] A more preferred therapy for the treatment of colon cancer
is a combination of therapeutically effective amounts of an
integrin antagonist in combination with the following
antineoplastic agents: fluorouracil, and Levamisole. Preferably,
fluorouracil and Levamisole are used in combination.
Example 3
[0308] Breast Cancer
[0309] Today, among women in the United States, breast cancer
remains the most frequent diagnosed cancer. One in 8 women in the
United States are at risk of developing breast cancer in their
lifetime. Age, family history, diet, and genetic factors have been
identified as risk factors for breast cancer. Breast cancer is the
second leading cause of death among women.
[0310] Different chemotherapeutic agents are known in art for
treating breast cancer. Cytoxic agents used for treating breast
cancer include doxorubicin, cyclophosphamide, methotrexate,
5-fluorouracil, mitomycin C, mitoxantrone, taxol, and epirubicin.
CANCER SURVEYS, Breast Cancer volume 18, Cold Spring Harbor
Laboratory Press, 1993.
[0311] In the treatment of locally advanced noninflammatory breast
cancer, integrin antagonists can be used to treat the disease in
combination with other integrin antagonists, or in combination with
surgery, radiation therapy, antiangiogenic agents or with
chemotherapeutic agents. Preferred combinations of chemotherapeutic
agents, radiation therapy and surgery that can be used in
combination with the present invention include, but are not limited
to the following combinations: 1) doxorubicin, vincristine, radical
mastectomy; 2) doxorubicin, vincristine, radiation therapy; 3)
cyclophosphamide, doxorubicin, 5-flourouracil, vincristine,
prednisone, mastecomy; 4) cyclophosphamide, doxorubicin,
5-flourouracil, vincristine, prednisone, radiation therapy; 5)
cyclophosphamide, doxorubicin, 5-flourouracil, premarin, tamoxifen,
radiation therapy for pathologic complete response; 6)
cyclophosphamide, doxorubicin, 5-flourouracil, premarin, tamoxifen,
mastectomy, radiation therapy for pathologic partial response; 7)
mastectomy, radiation therapy, levamisole; 8) mastectomy, radiation
therapy; 9) mastectomy, vincristine, doxorubicin, cyclophosphamide,
levamisole; 10) mastectomy, vincristine, doxorubicin,
cyclophosphamide; 11) mastecomy, cyclophosphamide, doxorubicin,
5-fluorouracil, tamoxifen, halotestin, radiation therapy; 12)
mastecomy, cyclophosphamide, doxorubicin, 5-fluorouracil,
tamoxifen, halotestin.
[0312] In the treatment of locally advanced inflammatory breast
cancer, integrin antagonists can be used to treat the disease in
combination with other antiangiogenic agents, or in combination
with surgery, radiation therapy or with chemotherapeutic agents.
Preferred combinations of chemotherapeutic agents, radiation
therapy and surgery that can be used in combination with the
present invention include, but or not limited to the following
combinations: 1) cyclophosphamide, doxorubicin, 5-fluorouracil,
radiation therapy; 2) cyclophosphamide, doxorubicin,
5-fluorouracil, mastectomy, radiation therapy; 3) 5-flurouracil,
doxorubicin, clyclophosphamide, vincristine, prednisone,
mastectomy, radiation therapy; 4) 5-flurouracil, doxorubicin,
clyclophosphamide, vincristine, mastectomy, radiation therapy; 5)
cyclophosphamide, doxorubicin, 5-fluorouracil, vincristine,
radiation therapy; 6) cyclophosphamide, doxorubicin,
5-fluorouracil, vincristine, mastectomy, radiation therapy; 7)
doxorubicin, vincristine, methotrexate, radiation therapy, followed
by vincristine, cyclophosphamide, 5-florouracil; 8) doxorubicin,
vincristine, cyclophosphamide, methotrexate, 5-florouracil,
radiation therapy, followed by vincristine, cyclophosphamide,
5-florouracil; 9) surgery, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by
radiation therapy, followed by cyclophosphamide, methotrexate,
5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine,
tamoxifen; 10) surgery, followed by cyclophosphamide, methotrexate,
5-fluorouracil, followed by radiation therapy, followed by
cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,
tamoxifen, doxorubicin, vincristine, tamoxifen; 11) surgery,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
predinsone, tamoxifen, followed by radiation therapy, followed by
cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin,
vincristine, tamoxifen; 12) surgery, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, followed by radiation therapy,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
predinsone, tamoxifen, doxorubicin, vincristine; 13) surgery,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
predinsone, tamoxifen, followed by radiation therapy, followed by
cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,
tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
followed by radiation therapy, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin,
vincristine; 15) surgery, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by
radiation therapy, followed by cyclophosphamide, methotrexate,
5-fluorouracil, doxorubicin, vincristine; 16) 5-florouracil,
doxorubicin, cyclophosphamide followed by mastectomy, followed by
5-florouracil, doxorubicin, cyclophosphamide, followed by radiation
therapy.
[0313] In the treatment of metastatic breast cancer, integrin
antagonists can be used to treat the disease in combination with
other antiangiogenic agents, or in combination with surgery,
radiation therapy or with chemotherapeutic agents. Preferred
combinations of chemotherapeutic agents that can be used in
combination with the integrin antagonists of the present invention
include, but are not limited to the following combinations: 1)
cyclosphosphamide, methotrexate, 5-fluorouracil; 2)
cyclophosphamide, adriamycin, 5-fluorouracil; 3) cyclosphosphamide,
methotrexate, 5-flurouracil, vincristine, prednisone; 4)
adriamycin, vincristine; 5) thiotepa, adriamycin, vinblastine; 6)
mitomycin, vinblastine; 7) cisplatin, etoposide.
Example 4
[0314] Prostate Cancer
[0315] Prostate cancer is now the leading form of cancer among men
and the second most frequent cause of death from cancer in men. It
is estimated that more than 165,000 new cases of prostate cancer
were diagnosed in 1993, and more than 35,000 men died from prostate
cancer in that year. Additionally, the incidence of prostate cancer
has increased by 50% since 1981, and mortality from this disease
has continued to increase. Previously, most men died of other
illnesses or diseases before dying from their prostate cancer. We
now face increasing morbidity from prostate cancer as men live
longer and the disease has the opportunity to progress.
[0316] Current therapies for prostate cancer focus exclusively upon
reducing levels of dihydrotestosterone to decrease or prevent
growth of prostate cancer. In addition to the use of digital rectal
examination and transrectal ultrasonography, prostate-specific
antigen (PSA) concentration is frequently used in the diagnosis of
prostate cancer.
[0317] A preferred therapy for the treatment of prostate cancer is
a combination of therapeutically effective amounts of an integrin
antagonist in combination with one or more additional
antiangiogenic agents.
[0318] U.S. Pat. No. 4,472,382 discloses treatment of benign
prostatic hyperplasia (BPH) with an antiandrogen and certain
peptides which act as LH-RH agonists.
[0319] U.S. Pat. No. 4,596,797 discloses aromatase inhibitors as a
method of prophylaxis and/or treatment of prostatic
hyperplasia.
[0320] U.S. Pat. No. 4,760,053 describes a treatment of certain
cancers which combines an LHRH agonist with an antiandrogen and/or
an antiestrogen and/or at least one inhibitor of sex steroid
biosynthesis.
[0321] U.S. Pat. No. 4,775,660 discloses a method of treating
breast cancer with a combination therapy which may include surgical
or chemical prevention of ovarian secretions and administering an
antiandrogen and an antiestrogen.
[0322] U.S. Pat. No. 4,659,695 discloses a method of treatment of
prostate cancer in susceptible male animals including humans whose
testicular hormonal secretions are blocked by surgical or chemical
means, e.g. by use of an LHRH agonist, which comprises
administering an antiandrogen, e.g. flutamide, in association with
at least one inhibitor of sex steroid biosynthesis, e.g.
aminoglutethimide and/or ketoconazole.
[0323] Prostate Specific Antigen
[0324] One well known prostate cancer marker is Prostate Specific
Antigen (PSA). PSA is a protein produced by prostate cells and is
frequently present at elevated levels in the blood of men who have
prostate cancer. PSA has been shown to correlate with tumor burden,
serve as an indicator of metastatic involvement, and provide a
parameter for following the response to surgery, irradiation, and
androgen replacement therapy in prostate cancer patients. It should
be noted that Prostate Specific Antigen (PSA) is a completely
different protein from Prostate Specific Membrane Antigen (PSMA).
The two proteins have different structures and functions and should
not be confused because of their similar nomenclature.
[0325] Prostate Specific Membrane Antigen (PSMA)
[0326] In 1993, the molecular cloning of a prostate-specific
membrane antigen (PSMA) was reported as a potential prostate
carcinoma marker and hypothesized to serve as a target for imaging
and cytotoxic treatment modalities for prostate cancer. Antibodies
against PSMA have been described and examined clinically for
diagnosis and treatment of prostate cancer. In particular,
Indium-111 labelled PSMA antibodies have been described and
examined for diagnosis of prostate cancer and itrium-labelled PSMA
antibodies have been described and examined for the treatment of
prostate cancer.
Example 5
[0327] Bladder Cancer
[0328] The classification of bladder cancer is divided into three
main classes: 1) superficial disease, 2) muscle-invasive disease,
and 3) metastatic disease.
[0329] Currently, transurethral resection (TUR), or segmental
resection, account for first line therapy of superficial bladder
cancer, i.e., disease confined to the mucosa or the lamina propria.
However, intravesical therapies are necessary, for example, for the
treatment of high-grade tumors, carcinoma in situ, incomplete
resections, recurrences, and multifocal papillary. Recurrence rates
range from up to 30 to 80 percent, depending on stage of
cancer.
[0330] Therapies that are currently used as intravesical therapies
include chemotherapy, immuontherapy, bacille Calmette-Guerin (BCG)
and photodynamic therapy. The main objective of intravesical
therapy is twofold: to prevent recurrence in high-risk patients and
to treat disease that cannot by resected. The use of intravesical
therapies must be balanced with its potentially toxic side effects.
Additionally, BCG requires an unimpaired immune system to induce an
antitumor effect. Chemotherapeutic agents that are known to be
inactive against superficial bladder cancer include Cisplatin,
actinomycin D, 5-fluorouracil, bleomycin, and cyclophosphamide
methotrxate.
[0331] In the treatment of superficial bladder cancer, integrin
antagonists can be used to treat the disease in combination with
other integrin antagonists, or in combination with surgery (TUR),
chemotherapy, antiangiogenic therapy and intravesical
therapies.
[0332] A preferred therapy for the treatment of superficial bladder
cancer is a combination of therapeutically effective amounts of an
integrin antagonist in combination with: thiotepa (30 to 60
mg/day), mitomycin C (20 to 60 mg/day), and doxorubicin (20 to 80
mg/day).
[0333] A preferred intravesicle immunotherapeutic agent that may be
used in the present invention is BCG. A preferred daily dose ranges
from 60 to 120 mg, depending on the strain of the live attenuated
tuberculosis organism used.
[0334] A preferred photodynamic therapuetic agent that may be used
with the present invention is Photofrin I, a photosensitizing
agent, administered intravenously. It is taken up by the
low-density lipoprotein receptors of the tumor cells and is
activated by exposure to visible light. Additionally, neomydium YAG
laser activation generates large amounts of cytotoxic free radicals
and singlet oxygen.
[0335] In the treatment of muscle-invasive bladder cancer, integrin
antagonists can be used to treat the disease in combination with
other integrin antagonists, antiangiogenic agents, or in
combination with surgery (TUR), intravesical chemotherapy,
radiation therapy, and radical cystectomy with pelvic lymph node
dissection.
[0336] A preferred radiation dose for the treatment of bladder
cancer is between 5,000 to 7,000 cGY in fractions of 180 to 200 cGY
to the tumor. Additionally, 3,500 to 4,700 cGY total dose is
administered to the normal bladder and pelvic contents in a
four-field technique. Radiation therapy should be considered only
if the patient is not a surgical candidate, but may be considered
as preoperative therapy.
[0337] A preferred combination of surgery and chemotherapeutic
agents that can be used in combination with the integrin
antagonists of the present invention is cystectomy in conjunction
with five cycles of cisplatin (70 to 100 mg/m(square)); doxorubicin
(50 to 60 mg/m(square); and cyclophosphamide (500 to 600
mg/m(square).
[0338] A more preferred therapy for the treatment of superficial
bladder cancer is a combination of therapeutically effective
amounts of an integrin antagonist plus one or more additional
antiangiogenesis agents including a matrix metalloproteinase
inhibitor (MMP), or a cyclooxygenase-II inhibitor (COX-II).
[0339] An even more preferred combination for the treatment of
superficial bladder cancer is a combination of therapeutically
effective amounts of an integrin antagonist in combination with the
following combinations of antineoplastic agents: 1) cisplatin,
doxorubicin, cyclophosphamide; and 2) cisplatin, 5-fluorouracil. An
even more preferred combination of chemotherapeutic agents that can
be used in combination with radiation therapy and the integrin
antagonists is a combination of cisplatin, methotrexate,
vinblastine.
[0340] Currently no curative therapy exists for metastatic bladder
cancer. The present invention contemplates an effective treatment
of bladder cancer leading to improved tumor inhibition or
regression, as compared to current therapies.
[0341] In the treatment of metastatic bladder cancer, integrin
antagonists can be used to treat the disease in combination with
other antiangiogenic agents, or in combination with surgery,
radiation therapy or with chemotherapeutic agents.
[0342] A preferred therapy for the treatment of metastatic bladder
cancer is a combination of therapeutically effective amounts of an
integrin antagonist plus one or more additional antiangiogenesis
agents including a matrix metalloproteinase inhibitor (MMP) or a
cyclooxygenase-II inhibitor (COX-II).
[0343] A more preferred combination for the treatment of metastatic
bladder cancer is a combination of therapeutically effective
amounts of one or more integrin antagonists in combination with the
following combinations of antineoplasitc agents: 1) cisplatin and
methotrexate; 2) doxorubicin, vinblastine, cyclophoshamide, and
5-fluorouracil; 3) vinblastine, doxorubicin, cisplatin,
methotrexate; 4) vinblastine, cisplatin, methotrexate; 5)
cyclophosphamide, doxorubicin, cisplatin; 6) 5-fluorouracil,
cisplatin.
Example 6
[0344] Pancreas Cancer
[0345] Approximately 2% of new cancer cases diagnoses in the United
States are pancreatic cancer. Pancreatic cancer is generally
classified into two clinical types: 1) adenocarcinoma (metastatic
and non-metastatic), and 2) cystic neoplasms (serous cystadenomas,
mucinous cystic neoplasms, papilary cystic neoplasms, acinar cell
systadenocarcinoma, cystic choriocarcinoma, cystic teratomas,
angiomatous neoplasms).
[0346] Preferred combinations of therapy for the treatment of
non-metastatic adenocarcinoma that may be used in the present
invention include the use of an integrin antagonist along with
preoperative bilary tract decompression (patients presenting with
obstructive jaundice); surgical resection, including standard
resection, extended or radial resection and distal pancreatectomy
(tumors of body and tail); antiangiogenic therapy, adjuvant
radiation; and chemotherapy.
[0347] For the treatment of metastatic adenocarcinoma, a preferred
combination therapy consists of an integrin antagonist of the
present invention in combination with continuous treatment of
5-fluorouracil, followed by weekly cisplatin therapy.
[0348] A more preferred combination therapy for the treatment of
cystic neoplasms is the use of an integrin antagonist along with
resection.
Example 7
[0349] Ovary Cancer
[0350] Celomic epithelial carcinoma accounts for approximately 90%
of ovarian cancer cases. A preferred therapy for the treatment of
ovary cancer is a combination of therapeutically effective amounts
of an integrin antagonist plus one or more antiangiogenesis agents
including a matrix metalloproteinase inhibitor (MMP) and/or a
cyclooxygenase-II inhibitor.
[0351] Preferred single agents that can be used in combination with
an integrin antagonist include, but are not limited to: alkylating
agents, ifosfamide, cisplatin, carboplatin, taxol, doxorubicin,
5-fluorouracil, methotrexate, mitomycin, hexamethylmelamine,
progestins, antiestrogens, prednimustine, dihydroxybusulfan,
galactitol, interferon alpha, and interferon gama.
[0352] Preferred combinations for the treatment of celomic
epithelial carcinoma is a combination of therapeutically effective
amounts of an integrin antagonist in combination with the following
combinations of antineoplastic agents: 1) cisplatin, doxorubicin,
cyclophosphamide; 2) hexamthylmelamine, cyclosphamide, doxorubicin,
cisplatin; 3) cyclophosphamide, hexamehtylmelamine, 5-flurouracil,
cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5)
melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide,
cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin,
hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin,
hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin;
10) hexamethylmelamine, doxorubicin, carboplatin; 11)
cyclophosphamide, hexamethlmelamine, doxorubicin, cisplatin; 12)
carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.
[0353] Germ cell ovarian cancer accounts for approximately 5% of
ovarian cancer cases. Germ cell ovarian carcinomas are classified
into two main groups: 1) dysgerminoma, and nondysgerminoma.
Nondysgerminoma is further classified into teratoma, endodermal
sinus tumor, embryonal carcinoma, chloricarcinoma, polyembryoma,
and mixed cell tumors.
[0354] A preferred therapy for the treatment of germ cell carcinoma
is a combination of therapeutically effective amounts of an
integrin antagonist plus one or more antiangiogenesis agents
including a matrix metalloproteinase inhibitor (MMP) and/or a
cyclooxygenase-II inhibitor.
[0355] A more preferred therapy for the treatment of germ cell
carcinoma is a combination of therapeutically effective amounts of
an integrin antagonist in combination with the following
combinations of antineoplastic agents: 1) vincristine, actinomycin
D, cyclophosphamide; 2) bleomycin, etoposide, cisplatin; 3)
vinblastine, bleomycin, cisplatin.
[0356] Cancer of the fallopian tube is the least common type of
ovarian cancer, accounting for approximately 400 new cancer cases
per year in the United States. Papillary serous adenocarcinoma
accounts for approximately 90% of all malignancies of the ovarian
tube.
[0357] A preferred therapy for the treatment of fallopian tube
cancer is a combination of therapeutically effective amounts of an
integrin antagonist plus one or more antiangiogenesis agents
including a matrix metalloproteinase inhibitor (MMP) and/or a
cyclooxygenase-II inhibitor.
[0358] A more preferred therapy for the treatment of fallopian tube
cancer is a combination of therapeutically effective amounts of an
integrin antagonist in combination with the following of
antineoplastic agents: alkylating agents, ifosfamide, cisplatin,
carboplatin, taxol, doxorubicin, 5-fluorouracil, methotrexate,
mitomycin, hexamethylmelamine, progestins, antiestrogens,
prednimustine, dihydroxybusulfan, galactitol, interferon alpha, and
interferon gama.
[0359] An even more preferred therapy for the treatment of
fallopian tube cancer is a combination of therapeutically effective
amounts of an integrin antagonist in combination with the following
combinations of antineoplastic agents: 1) cisplatin, doxorubicin,
cyclophosphamide; 2) hexamthylmelamine, cyclosphamide, doxorubicin,
cisplatin; 3) cyclophosphamide, hexamehtylmelamine, 5-flurouracil,
cisplatin; 4) melphalan, hexamethylmelamine, cyclophosphamide; 5)
melphalan, doxorubicin, cyclophosphamide; 6) cyclophosphamide,
cisplatin, carboplatin; 7) cyclophosphamide, doxorubicin,
hexamethylmelamine, cisplatin; 8) cyclophosphamide, doxorubicin,
hexamethylmelamine, carboplatin; 9) cyclophosphamide, cisplatin;
10) hexamethylmelamine, doxorubicin, carboplatin; 11)
cyclophosphamide, hexamethlmelamine, doxorubicin, cisplatin; 12)
carboplatin, cyclophosphamide; 13) cisplatin, cyclophosphamide.
Example 8
[0360] Central Nervous System Cancers
[0361] Central nervous system cancer accounts for approximately 2%
of new cancer cases in the United States. Common intracranial
neoplasms include glioma, meninigioma, neurinoma, and adenoma.
[0362] A preferred therapy for the treatment of central nervous
system cancers is a combination of therapeutically effective
amounts of an integrin antagonist plus one or more antiangiogenesis
agents including a matrix metalloproteinase inhibitor (MMP) and/or
a cyclooxygenase-II inhibitor.
[0363] A preferred therapy for the treatment of maligant glioma is
a combination of therapeutically effective amounts of an integrin
antagonist in combination with the following combinations of
therapies and antineoplastic agents: 1) radiation therapy, BCNU
(carmustine); 2) radiation therapy, methyl CCNU (lomustine); 3)
radiation therapy, medol; 4) radiation therapy, procarbazine; 5)
radiation therapy, BCNU, medrol; 6) hyperfraction radiation
therapy, BCNU; 7) radiation therapy, misonidazole, BCNU; 8)
radiation therapy, streptozotocin; 9) radiation therapy, BCNU,
procarbazine; 10) radiation therapy, BCNU, hydroxyurea,
procarbazine, VM-26; 11) radiation therapy, BNCU, 5-flourouacil;
12) radiation therapy, Methyl CCNU, dacarbazine; 13) radiation
therapy, misonidazole, BCNU; 14) diaziquone; 15) radiation therapy,
PCNU; 16) procarbazine (matulane), CCNU, vincristine. A preferred
dose of radiation therapy is about 5,500 to about 6,000 cGY.
Preferred radiosensitizers include misonidazole, intra-arterial
Budr and intravenous iododeoxyuridine (IUdR). It is also
contemplated that radiosurgery may be used in combinations with
integrin antagonists.
Biological Evaluation
[0364] Integrin Antagonists
[0365] 1.
[0366] Cancer cells were implanted subcutaneously in genetically
engineered mice and grew large-volume tumors (>1,500 mm.sup.3).
Subsequent administration of compound I7 reduced tumor growth by as
much as 85 percent in a dose dependent manner. (Nickols A, et al.
Inhibition of tumor growth and metastasis by an .alpha.v.beta.3
integrin antagonist. Presented at the 89.sup.th Annual Meeting of
the American Association for Cancer Research, March, 1998.)
[0367] 2.
[0368] In an additional experiment, tumor cells were implanted into
mice; lung tumors of volumes greater than 2,000 mm.sup.3were
developed. The mice were then separated into four groups, including
a control group and three treatment groups: compound I7 alone;
compound I7 with cisplatin (a cytotoxic drug); or cisplatin alone.
Compared to the control groups, the mice treated with combination
compound I7/cisplatin therapy experienced more than an 80 percent
reduction in tumor size. In comparison, the group receiving
cisplatin alone experienced 50 percent reductions in tumor size and
the compound I7 group experienced 20-30 percent reductions. These
studies indicate that compound I7 has prominent anti-tumor
activity.
[0369] 3. M21 human melanoma, rat Leydig testicular carcinoma,
Lewis Lung and human xenograft models:
[0370] To test the utility of a.sub.vb.sub.3 antagonists as single
agents and in combination chemotherapy, the M21 human melanoma, rat
Leydig testicular carcinoma, and the Lewis Lung carcinoma (LLC)
model as well as other human tumor xenograft models were utilized.
Tumor cells for implantation were taken from cells either grown in
tissue culture (Leydig, M21) or serially passaged as tumors in mice
and prepared as tumor brei (LLC). Mice were injected subcutaneously
in the proximal dorsal midline with 5.times.10.sup.6 tumor cells
and administration of test compound or vehicle was initiated the
evening of the same day. Tumor volumes were measured at intervals
over the course of the experiments. Tumors were measured with a
vernier caliper and volumes were determined using the formula for
the volume of a cylinder: tumor
volume=width.sup.2.times.length.times.0.52. Blood was routinely
drawn for plasma drug concentration 6 hours post-dosing on day 4 or
5 and again 12 hours post-dosing on the day of sacrifice. On the
final day of the experiment, tumors were dissected free and
weighed. The data are expressed as the mean +/-SEM. Student's and
Mann-Whitney tests were used to assess differences between means or
medians using the InStat software package.
[0371] In the LLC model, compound I7 was administered continuously
beginning on day 1 after implantation of the tumor cells, and the
chemotherapeutic, cisplatin, was administered as a single
intraperitoneal dose of 10 mg/kg on day 5. In this study, cisplatin
alone significantly retarded the growth of the LLC tumor
(p<0.05). Compound I7 (1 and 10 mg/kg, BID, PO) did not affect
the growth of the primary tumor mass. However, the combination of
compound I7 together with cisplatin resulted in an additive effect
and a significant tumor growth delay (time to develop a
tumor>500 mm.sup.3 was: vehicle=18.1 days; cisplatin=22.4 days;
cisplatin+compound I7 (10 mg/kg)=27.3 days). The final tumor volume
was also significantly reduced with the combination of cisplatin
and compound I7 producing a reduction of final tumor volume of 68%
in combination (p<0.05). Moreover, the combination of cisplatin
and compound I7 resulted in a 39% improvement in median survival
time over vehicle controls and an enhancement over either agent
alone (28 days for the vehicle group; 33 days for the cisplatin
group; 33 days for the compound I7 at 10 mg/kg group; 38 days for
the combination group). Similarly, compound I7 reduced tumor volume
when given with cisplatin in a dose-sequencing protocol. The
combination of a.sub.vb.sub.3 antagonist and chemotherapeutic agent
was more efficacious than cisplatin alone, particularly when
therapy with compound I7 (po, BID) was begun at the same time as
cisplatin (once, IP on day 5) or 5 days later (p<0.05 or less
for all).
[0372] In the M21 model, M21 human melanoma cells implanted
subcutaneously into SCID mice developed tumors which grew to
approximately 400 mm.sup.3 within 30 days. Oral administration of
compound compound I7 (BID) dose-dependently retarded the growth of
these tumors when administered at the time of tumor implantation or
beginning up to 21 days after implantation. Time to develop a tumor
mass>200 mm.sup.3 was significantly lengthened in the group
treated with the a.sub.vb.sub.3 antagonist (time to tumor
volume>200 mm.sup.3 was: vehicle=15 days; compound I7, 10
mg/kg=27 days). These data clearly demonstrate the utility of
compound compound I7 to inhibit the growth of pre-existing and
established tumors. Moreover, compound compound I7 increased the
antitumor efficacy of cisplatin when treatment with the
a.sub.vb.sub.3 antagonist was begun on day 1, prophylactically, or
therapeutically, on day 14 or 17 (all combinations significantly
less than cisplatin alone, p<0.05). Cisplatin was administered
once by ip injection (10 mg/kg) on day 14. Final tumor weights were
nearly identical in the combination treated groups, with clear
enhancement of the effect of cisplatin treatment alone. The results
of this dose sequencing experiment establish the efficacy of
compound I7 in combination therapy with cisplatin when administered
before, concurrent with, or after cisplatin dosing.
[0373] The Rice 500 rat Leydig testicular tumor grows very quickly
when implanted into the flank of SCID mice. Compound I7 inhibited
tumor growth dose-dependently when given in the drinking water at
concentrations of 0.02 to 2 mg/ml. Tumor growth was reduced by
about 50% at the 2 mg/ml dose in this aggressive model. Since the
tumor does not express the a.sub.vb.sub.3 integrin, the antitumor
effects were likely to be produced by the inhibition of
angiogenesis. Similar to the results seen in the M21 tumor model,
compound I7 increased the effects of cisplatin in the Leydig tumor
model. Indeed, the combination of cisplatin and compound I7 was
almost 100% effective in preventing tumor growth over the 11 day
course of the study. Dose-related inhibition of tumor growth by
compound I7 (10 or 100 mg/kg, BID, PO) was also seen when the
compound was given as monotherapy or in combination with cisplatin
(10 mg/kg, ip once on day 5) (p<0.01 vs control). Therapeutic
treatment with the a.sub.vb.sub.3 antagonist was begun at the same
time as cisplatin on day 5, with tumor volumes of about 200
mm.sup.3 at the initiation of therapy. In a similar experiment, the
effects of compound I7, cisplatin and the combination were
evaluated for potentiation of overall survival in the Leydig tumor
mice. Survival was increased by either compound I7 or cisplatin
alone when compared to vehicle treated controls (p<0.05). More
importantly, the combination of the two agents almost doubled
overall survival (from 17 to 29 days) (p<0.01 combination vs.
cisplatin, p<0.001 combination vs. control). Thus, the ability
of compound I7 to work alone or in combination therapy to prevent
tumor growth clearly correlates with enhanced survival.
[0374] 4. U251 Glioblastoma Model:
[0375] compound I7 was evaluated in the human U251 glioblastoma
model. The tumors were implanted onto the flanks of SCID mice and
the mean tumor volume with time was calculated. In this model, at
the dose tested (10 mg/kg, BID, PO), compound I7 produced little
inhibition of tumor growth by itself when administered from day 14
through 44. The chemotherapeutic agent, BCNU (12 mg/kg)
administered once a day on days 14, 18 and 22, induced a regression
of the tumors to the limit of detectability, but the tumors grew
back. Combination treatment with BCNU and compound I7 regressed
tumors to the limit of dectability throughout the period of
treatment (compound I7 administered from day 14-44) and almost
through the rest of the study. When the data are examined as time
to tumor progression (days to 2 tumor doublings), there is clear
enhancement by the drug combination over the antitumor effects of
either agent alone (p<0.0l). Moreover, the response rate
(responders to BCNU) is markedly enhanced and the duration of the
response is increased 5-fold from 5 days to 25 days (p<0.01).
These clinically relevant measurements of antitumor efficacy
establish the antitumor efficacy of compound I7, especially when
combined with standard of care chemo therapeutic agents.
[0376] 5. A2780 Mouse Model:
[0377] compound I7 prevents the growth of human ovarian carcinoma
in SCID mice. The A2780 tumor line is another aggressive tumor
model characterized by rapid growth. compound I7 treatment (10
mg/kg, BID, PO) was equally effective as cisplatin (10 mg/kg, ip
once on day 20) in decreasing tumor growth. However, as seen in the
other tumor models, compound I7 potentiated the effects of
cisplatin, resulting in an 80% reduction vs control on day 30.
Survival studies are now underway to characterize the survival
benefit of combination therapy in this model.
[0378] 6. Corneal Micropocket Assay:
[0379] In this model, an intrastromal pocket is surgically created
in the normally avascular cornea of female C57BL6 mice 1 mm
distance from the corneal-scleral junction. A slow release hydron
polymer pellet containing an angiogenic growth factor (bFGF or
VEGF) is inserted into the corneal pocket. The pocket is self
sealing and antibiotic ointment is placed in the eye. Five days
later the eyes are examined under a slit lamp and the neovascular
response is quantitated by measuring the average vessel length (VL)
and the contiguous circumferential zone (CH=clock hours where 1
CH=30 degrees) and plugged into the formula of half an ellipse;
Area (mm2)=0.5.times.3.1416.times.VL.times.CH.times.0.4. compound
I7 administered BID is a potent inhibitor of angiogenesis in the
mouse corneal micropocket model. compound I7 dose-dependently
inhibited the angiogenic response up to 42% with maximal inhibitory
activity observed at doses of 10 mg/kg, BID orally. Moreover,
compound I7 inhibited angiogenesis induced by either bFGF or VEGF,
the two predominant growth factors known to be produced by tumor
cells in vivo. These data confirm the mechanism of action of
compound I7 as direct inhibition of angiogenesis in vivo.
[0380] 7. Metastasis
[0381] Accurate quantitation of early-stage metastasis in animal
models is typically hampered by the lack of sensitive and
convenient assays to detect low numbers of tumor cells in a
background of normal tissue. Quantitation of late-stage metastasis
by counting of visible foci or comparison of organ weights requires
substantial tumor burden which can take 3-4 months to develop in
conventional models of breast cancer, and generally cannot detect
subtle differences. To develop a more quantitative metastasis model
in which the effect of inhibitors on multiple stages of the
metastatic process could be dissected, we have produced stable
MDA-MB-435 breast carcinoma cell lines expressing a synthetic
variant of green fluorescent protein (GFP). The GFP-transfected
cells are easily detected by flow cytometry, and fixation of the
cells or the addition of antibodies or exogenous substrates is not
required. A highly aggressive clone was isolated from the lung of a
SCID mouse implanted in the mammary fat pad with several
GFP-expressing clones. This line, designated 435/GFP HAL-1,
consistently generates substantial tumor burden in the lungs by 8-9
weeks compared with 12-16 weeks for the parent line. As few as 1
tumor cell in 200,000 host cells can be detected by flow cytometry,
and fluorescent cells are detected in the lungs and blood as early
as one week post-orthotopic implantation. compound I7 was
administered at doses of 1, 10, and 30 mg/kg, BID, orally following
orthotopic surgical implantation of 435/GFP HAL-1 cells into the
mammary fat pad of SCID mice. Eight weeks later, lungs were removed
and weighed. Metastasis was quantitated using a semi-quantitative
visible scoring method of gross metastases under a dissecting scope
or, following dissection and disaggregation of lung tissue, by flow
cytometry of GFP expressing cells. compound I7 administration
dose-dependently reduced the spontaneous metastasis of 435 breast
carcinoma cells to the lungs as determined either by direct visual
counting or quantitation by flow cytometry. Doses of 10 and 30
mg/kg resulted in a 55% and 69% reduction in lung metastatic
burden, respectively. However, compound I7 did not delay the growth
of the primary tumor mass in this model. Histological examination
of lung sections from these studies revealed a dramatic reduction
in the number of large macroscopic metastases and an increase in
the presence of microscopic foci of metastases in the compound I7
treated animals.
* * * * *