U.S. patent application number 10/461983 was filed with the patent office on 2004-03-18 for combination therapy of radiation and a cox-2 inhibitor for the treatment of neoplasia.
Invention is credited to Masferrer, Jaime L..
Application Number | 20040053935 10/461983 |
Document ID | / |
Family ID | 26811473 |
Filed Date | 2004-03-18 |
United States Patent
Application |
20040053935 |
Kind Code |
A1 |
Masferrer, Jaime L. |
March 18, 2004 |
Combination therapy of radiation and a COX-2 inhibitor for the
treatment of neoplasia
Abstract
The present invention provides methods to treat or prevent
neoplasia disorders in a mammal using a combination of radiation
therapy and a cyclooxygenase-2 inhibitor.
Inventors: |
Masferrer, Jaime L.;
(Ballwin, MO) |
Correspondence
Address: |
Pharmacia Corporation
Corporate Patent Department
P.O. Box 1027
Chesterfield
MO
63006
US
|
Family ID: |
26811473 |
Appl. No.: |
10/461983 |
Filed: |
June 13, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10461983 |
Jun 13, 2003 |
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09385214 |
Aug 27, 1999 |
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6649645 |
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60113786 |
Dec 23, 1998 |
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Current U.S.
Class: |
514/252.05 ;
514/406; 514/473; 600/1 |
Current CPC
Class: |
A61K 31/445 20130101;
A61K 31/505 20130101; A61K 41/00 20130101; A61K 45/06 20130101;
A61P 35/00 20180101; A61K 31/135 20130101; A61K 33/243 20190101;
A61K 31/415 20130101; A61K 31/675 20130101; A61P 43/00 20180101;
A61K 31/42 20130101; A61K 31/506 20130101; A61K 41/0038 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: |
514/252.05 ;
514/406; 514/473; 600/001 |
International
Class: |
A61K 031/501; A61K
031/415; A61K 031/365; A61N 005/00 |
Claims
What is claimed is:
1. A method for treating neoplasia in a subject in need of such
treatment, the method comprises treating the subject with radiation
therapy and a therapeutically effective amount of a
cyclooxygenase-2 inhibitor or pharmaceutically-acceptable or
derivative thereof.
2. The method of claim 1 wherein the neoplasia is selected from
lung cancer, breast cancer, gastrointestinal cancer, bladder
cancer, head and neck cancer and cervical cancer.
3. A method for treating neoplasia in a subject in need of such
treatment, the method comprises treating the subject with radiation
therapy and a therapeutically effective amount of a
cyclooxygenase-2 inhibitor or pharmaceutically-acceptable or
derivative thereof, wherein the cyclooxygenase-2 inhibitor is
selected from compounds, and their pharmaceutically acceptable
salts, of the group consisting of 910111213141516
4. A method for treating neoplasia in a subject in need of such
treatment, the method comprises treating the subject with radiation
therapy and a therapeutically effective amount of a
cyclooxygenase-2 inhibitor or pharmaceutically-acceptable or
derivative thereof, wherein the cyclooxygenase-2 inhibitor is
selected from compounds, and their pharmaceutically acceptable
salts, of the group consisting of
5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazo-
le;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluorom-
ethyl)pyrazole;
4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)-
benzenesulfonamide
4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfo- namide;
4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide;
4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide;
4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonami-
de;
4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfona-
mide;
4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzene-
sulfonamide;
4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide;
4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesul-
fonamide;
4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzene-
sulfonamide;
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-
zenesulfonamide;
4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyr-
azol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H--
pyrazol-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-
-1-yl]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyr-
azol-1-yl]benzenesulfonamide;
4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-y- l]benzenesulfonamide;
4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1-
H-pyrazol-1-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-(trif-
luoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
4-[4-chloro-5-phenyl-1H-p- yrazol-1-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-
-pyrazol-1-yl]benzenesulfonamide;
4-[5-(4-(N,N-dimethylamino)phenyl)-3-(tr-
ifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4- -(methylsulfonyl)phenyl] spiro
[2.4]hept-5-ene; 4-[6-(4-fluorophenyl)spiro-
[2.4]hept-5-en-5-yl]benzenesulfonamide;
6-(4-fluorophenyl)-7-[4-(methylsul-
fonyl)phenyl]spiro[3.4]oct-6-ene;
5-(3-chloro-4-methoxyphenyl)-6-[4-(methy-
lsulfonyl)phenyl]spiro[2.4]hept-5-ene;
4-[6-(3-chloro-4-methoxyphenyl)spir-
o[2.4]hept-5-en-5-yl]benzenesulfonamide;
5-(3,5-dichloro-4-methoxyphenyl)--
6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene;
5-(3-chloro-4-fluorophen- yl)-6-[4-(methylsulfonyl)phenyl] spiro
[2.4]hept-5-ene;
4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide;
2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-
thiazole;
2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-
thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole;
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole;
2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)p-
henyl]thiazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluorom-
ethylthiazole;
1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopen-
ta-2,4-dien-3-yl]benzene;
4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-
-dien-3-yl]benzenesulfonamide;
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phe- nyl]spiro[2.4]hepta-4,
6-diene; 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-d-
ien-5-yl]benzenesulfonamide;
6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulf-
onyl)phenyl]-pyridine-3-carbonitrile;
2-bromo-6-(4-fluorophenyl)-5-[4-(met-
hylsulfonyl)phenyl]-pyridine-3-carbonitrile;
6-(4-fluorophenyl)-5-[4-(meth-
ylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile;
4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenes-
ulfonamide;
4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1--
yl]benzenesulfonamide;
4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H--
imidazol-1-yl]benzenesulfonamide;
3-[1-[4-(methylsulfonyl)phenyl]-4-(trifl-
uoromethyl)-1H-imidazol-2-yl]pyridine;
2-[1-[4-(methylsulfonyl)phenyl-4-(t-
rifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methyl-4-[1-[4-(methylsulfony-
l)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;
2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-
-yl]pyridine;
4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol--
1-yl]benzenesulfonamide;
2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)pheny-
l]-4-(trifluoromethyl)-1H-imidazole;
4-[2-(4-methylphenyl)-4-(trifluoromet-
hyl)-1H-imidazol-1-yl]benzenesulfonamide;
2-(4-chlorophenyl)-1-[4-(methyls-
ulfonyl)phenyl]-4-methyl-1H-imidazole;
2-(4-chlorophenyl)-1-[4-(methylsulf-
onyl)phenyl]-4-phenyl-1H-imidazole;
2-(4-chlorophenyl)-4-(4-fluorophenyl)--
1-[4-(methylsulfonyl)phenyl]-1H-imidazole;
2-(3-fluoro-4-methoxyphenyl)-1--
[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H imidazole;
1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;
2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imid-
azole;
4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl-
]benzenesulfonamide;
2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phen-
yl]-4-(trifluoromethyl)-1H imidazole;
4-[2-(3-fluoro-5-methylphenyl)-4-(tr-
ifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide;
2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imid-
azole;
4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesul-
fonamide;
1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethy-
l-1H-1-imidazole;
4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl-
]benzenesulfonamide;
4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzen-
esulfonamide;
4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazo-
l-1-yl]benzenesulfonamide;
1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl-
)phenyl]-5-(trifluoromethyl)-1H-pyrazole;
4-[1-ethyl-4-(4-fluorophenyl)-5--
(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide;
N-phenyl-[4-(4-luorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluorometh-
yl)-1H-pyrazol-1-yl]acetamide; ethyl
[4-(4-fluorophenyl)-3-[4-(methylsulfo-
nyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyra-
zole;
4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5--
(trifluoromethyl)pyrazole;
1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl-
)phenyl]-5-(trifluoromethyl)-1H-pyrazole;
5-(4-fluorophenyl)-4-(4-methylsu-
lfonylphenyl)-2-trifluoromethyl-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-
-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromet-
hyl)pyridine;
2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(-
trifluoromethyl)pyridine;
5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]--
2-(2-propynyloxy)-6-(trifluoromethyl)pyridine;
2-bromo-5-(4-fluorophenyl)--
4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine;
4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide;
1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene;
5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole;
4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide;
4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide;
1-[2-(4-fluorophenyl) cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene-
; 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(2,4-dichlorophenyl)
cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene-
;
1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)ben-
zene;
4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamid-
e;
1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)b-
enzene;
4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonam-
ide; 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide;
1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene;
4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide;
1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzen-
e;
4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide;
4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide;
ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)
phenyl]oxazol-2-yl]-2-benzyl-- acetate;
2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]ace-
tic acid;
2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]ox-
azole;
4-(4-fluorophenyl)-5-[(4-(methylsulfonyl)phenyl]-2-phenyloxazole;
4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole;
and
4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfo-
namide.
5. The method of claim 4 wherein the cyclooxygenase-2 inhibitor is
4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonam-
ide.
Description
RELATED CASE
[0001] This application is a continuation-in-part of U.S. patent
application Serial No. 60/113,786, filed Dec. 23, 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to a combination of radiation
therapy and a cyclooxygenase-2 (COX-2) inhibitor for treatment of
neoplasia disorders. More specifically, this invention relates to
the use of COX-2 inhibitors in combination with radiation therapy
for treating cancer.
BACKGROUND OF THE INVENTION
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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, inaccessible to
surgeons, nor in the treatment of disseminated neoplastic
conditions such as leukemia.
[0007] Chemotherapy involves the disruption of cell replication or
cell metabolism. It is used most often in the treatment of breast,
lung, and testicular cancer.
[0008] 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 such as pruritis, urticaria, and
angioedema; neurological complications; pulmonary and cardiac
complications in patients receiving radiation or chemotherapy; and
reproductive and endocrine complications (M. Abeloff, et al.,
Alopecia and Cutaneous Complications, in Clinical Oncology 755-56
(Abeloff, ed. 1992).
[0009] Chemotherapy-induced side effects significantly impact the
quality of life of the patient and may dramatically influence
patient compliance with treatment.
[0010] 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.
[0011] In general, radiation therapy is employed as potentially
curative therapy for patients who present with clinically localized
disease and are expected to live at least 10 years.
[0012] For example, approximately 70% of newly diagnosed prostate
cancer patients fall into this category. Approximately 10% of these
patients (7% of total patients) undergo radiation therapy.
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 radiotherapy patients generally do not receive any immediate
follow-up therapy. Rather, they are monitored frequently, such as
for elevated Prostate Specific Antigen ("PSA"), which is the
primary indicator of recurrence or metastasis in prostate
cancer.
[0013] The adverse side effects induced by chemotherapeutic agents
and radiation therapy have become of major importance to the
clinical management of cancer patients.
[0014] Colorectal Cancer 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.
[0015] 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.
[0016] Prostate Cancer
[0017] 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.
[0018] Current therapies for prostate cancer focus upon reducing
levels of dihydrotestosterone to decrease or prevent growth of
prostate cancer. Radiation alone or in combination with surgery
and/or chemotherapeutic agents is often used.
[0019] 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.
[0020] 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. U.S. Pat. No. 4,596,797
discloses aromatase inhibitors as a method of prophylaxis and/or
treatment of prostatic hyperplasia. 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. 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. 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.
[0021] Prostate Specific Antigen
[0022] 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.
[0023] Prostate Specific Membrane Antigen (PSMA)
[0024] 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 PSMK 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.
[0025] Pancreas Cancer
[0026] Approximately 2% of new cancer cases diagnoses in the United
States is 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).
[0027] Ovary Cancer
[0028] Celomic epithelial carcinoma accounts for approximately 90%
of ovarian cancer cases. Preferred single agents that can be used
in combination include: alkylating agents, ifosfamide, cisplatin,
carboplatin, taxol, doxorubicin, 5-fluorouracil, methotrexate,
mitomycin, hexamethylmelamine, progestins, antiestrogens,
prednimustine, dihydroxybusulfan, galactitol, interferon alpha and
interferon gamma.
[0029] 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.
[0030] Prostaglandins are arachidonate metabolites produced in
virtually all mammalian tissues and possess diverse biologic
capabilities, including vasoconstriction, vasodilation, stimulation
or inhibition of platelet aggregation, and immunomodulation,
primarily immunosupression (Moskowitz and Coughlins, Stroke 1981;
12: 882-86; Leung and Mihich. Nature 1980; 597-600; Brunda et al.,
J. Immunol. 1980; 124: 2682-7). They are implicated in the
promotion of development and growth of malignant tumors (Honn et
al., Prostaglandins 1981;21:833-64; Furuta et al., Cancer Res.
1989, 48, 3002-7; Taketo; J. Natl. Cancer Inst. 1998, 90, 160920).
They are also involved in the response of tumor and normal tissues
to cytotoxic agents such as ionizing radiation (Milas and Hanson,
Eur. J. Cancer 1995, 31A, 1580-5). Prostaglandin production is
mediated by two cyclooxygenase enzymes: COX-1 and COX-2.
Cyclooxygenase-1 (COX-1) is constitutively expressed and is
ubiquitous. Cyclooxygenase-2 (COX-2) is induced by diverse
inflammatory stimuli (Isakson et al., Adv. Pros. Throm. Leuk Res.
1995, 23, 49-54).
[0031] Prostaglandin-mediated effects at both the
microenvironmental and cellular levels have been implicated in the
modulation of such response. Prostaglandin E.sub.2, and
prostaglandin I.sub.2 protect jejunum crypt cells, and
prostaglandin I.sub.2 protects B16 melanoma cells from radiation
damage. Inhibition of prostaglandin synthesis also induces an
accumulation of cells in the G.sub.2+M phases of the cell cycle,
which are generally considered to be the most sensitive to ionizing
radiation. With the inhibition of prostaglandin synthesis,
prostaglandin-induced immunosuppressive activity was diminished and
antitumor immunologic responses were able to potentiate tumor
response to radiation. Finally, prostaglandins are vasoactive
agents and are thus likely to regulate tumor blood flow and
perfusion.
[0032] Nonsteroidal anti-inflammatory drugs (NSAIDs)
non-selectively inhibit both cyclooxygenase enzymes and
consequently can prevent, inhibit, or abolish the effects of
prostaglandins. Increasing evidence shows that NSAIDs can inhibit
the development of cancer in both experimental animals and in
humans, can reduce the size of established tumors, and can increase
the efficacy of cytotoxic cancer chemotherapeutic agents. Our own
investigations have demonstrated that indomethacin prolongs tumor
growth delay and increases the tumor cure rate in mice after
radiotherapy (Milas et al., Cancer Res. 1990, 50, 4473-7). The
influence of oxyphenylbutazone and radiation therapy on cervical
cancer has been studied. (Weppelmann and Monkemeier, Gyn. Onc.,
1984, 47, 196-9).
[0033] However, treatment with NSAIDs are limited by toxicity to
normal tissue, particularly by ulcerations and bleeding in the
gastrointestinal tract, ascribed to the inhibition of COX-1.
Recently developed selective COX-2 inhibitors exert potent
anti-inflammatory activity but cause fewer side effects.
[0034] Antiangiogenesis therapy has been used as an adjunct to
chemotherapy, radiation therapy, or surgery. (Kumar and Armstrong,
Emerging Drugs 1997, 2, 175-190). Recently, it was reported that
the combination of radiation with antiangiogenic compounds produces
an additive effect on the growth of human tumor xenografts (Gorski
et al., Cancer Res. 1998; 58, 5686-9).
[0035] COX-2 inhibitors have been described for the treatment of
cancer (WO98/16227) and for the treatment of tumors (EP 927,555).
Celecoxib, a specific inhibitor of COX-2, exerted a potent
inhibition of fibroblast growth factor-induced corneal angiogenesis
in rats. (Masferrer et al., Proc. Am. Assoc. Cancer Research 1999,
40, 396). COX-2 specific inhibitors prevent angiogenesis in
experimental animals, but their efficacy in enhancing in vivo tumor
response to radiation has not been established.
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] FIG. 1 shows the effect of a COX-2 inhibitor
(4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonami-
de) on tumor growth.
[0037] FIG. 2 shows the effect of a COX-2 inhibitor
(4-[5-(4-chlorophenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonami-
de) in combination with local tumor irradiation on tumor
growth.
[0038] FIG. 3 shows the effect of a COX-2 inhibitor on
dose-dependent and radiation-induced delay in tumor growth.
[0039] FIG. 4 shows the effect of a COX-2 inhibitor on tumor cure
by radiation.
DETAILED DESCRIPTION OF THE INVENTION
[0040] Treatment of a neoplasia disorder in a mammal in need of
such treatment is provided by methods and combinations using
radiation and a COX-2 inhibitor. The method comprises treating a
mammal with a therapeutically effective amount of a combination
comprising a COX-2 inhibitor and a radiotherapeutic agent.
[0041] Specific inhibitors of COX-2 potentiate tumor response to
radiation. Thus, COX-2 inhibitors improve the efficacy of
radiotherapy.
[0042] The methods and combinations of the present invention may be
used for the treatment of neoplasia disorders selected from 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, chondrosarcoma, 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, undifferentiatied carcinoma, uveal melanoma, verrucous
carcinoma, vipoma, well differentiated carcinoma, and Wilm's
tumor.
[0043] The methods and compositions of the present invention
provide one or more benefits. A combination of a COX-2 inhibitor
with radiation therapy of the present invention are useful in
treating neoplasia disorders. Preferably, the COX-2 inhibitor agent
or agents and the radiation 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 for each
of the individual components administered alone.
[0044] A benefit of lowering the dose of the radiation therapies of
the present invention administered to a mammal includes a decrease
in the incidence of adverse effects associated with higher
dosages.
[0045] 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, and a
reduction in the number of hospitalizations needed for the
treatment of adverse effects.
[0046] Alternatively, the methods and combination of the present
invention can also maximize the therapeutic effect at higher
doses.
[0047] The term "pharmaceutically acceptable" is used 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.
[0048] Also included in the combination of the invention are the
isomeric forms 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, .beta.-hydroxybutyric, galactaric
and galacturonic acids.
[0049] 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.
[0050] A COX-2 inhibitor 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 and
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980.
[0051] 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 diluent 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.
[0052] 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 solid at ordinary
temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
[0053] 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.
[0054] 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
COX-2 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.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] The term "prevention," in relation to neoplasia, tumor
growth or tumor cell growth, means no tumor or tumor cell growth if
none had occurred, no further tumor or tumor cell growth if there
had already been growth.
[0060] 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 specific
COX-2 inhibitors, that prevent the growth of cells that form new
blood vessels.
[0061] 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
incidence over treatment of each agent by itself, while avoiding
adverse side effects typically associated with alternative
therapies.
[0062] A "therapeutic effect" relieves to some extent one or more
of the symptoms of a neoplasia disorder. In reference to the
treatment of a cancer, a therapeutic effect refers to one or more
of the following: 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; 4) inhibition (i.e., slowing to some extent,
preferably stopping) of tumor metastasis; 5) inhibition, to some
extent, of tumor growth; 6) relieving or reducing to some extent
one or more of the symptoms associated with the disorder; and/or 7)
relieving or reducing the side effects associated with the
administration of anticancer agents.
[0063] "Therapeutic effective amount" is intended to qualify the
amount required to achieve a therapeutic effect.
[0064] The phrases "low dose" or "low dose amount", in
characterizing a therapeutically effective amount of the COX-2
inhibitor and the radiation or therapy in the combination therapy,
defines a quantity of such therapy, or a range of quantity of such
therapy, that is capable of diminishing the neoplastic disease
while reducing or avoiding one or more radiation-induced side
effects, such as myelosupression, cardiac toxicity, skin erythema
and desquamation, alopecia, inflammation or fibrosis.
[0065] The phrase "adjunctive therapy" includes agents such as
those, 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.
[0066] The phrase a "radiotherapeutic agent" refers to the use of
electromagnetic or particulate radiation in the treatment of
neoplasia. Examples of radiotherapeutic agents are provided in, but
not limited to, radiation therapy and is known in the art (Hellman,
Principles of Radiation Therapy, Cancer, in Principles and Practice
of Oncology, 248-75 (Devita et al., ed., 4.sup.th edit., volume 1,
1993).
[0067] The phrase "COX-2 inhibitor" includes agents that
specifically inhibit a class of enzymes, the COX-2 enzyme.
Preferably, it includes compounds which have a COX-2 IC.sub.50 of
less than about 1.0 .mu.M, and more preferably of less than about
0.1 .mu.M, and also have a selectivity ratio of COX-2 inhibition
over COX-1 inhibition of at least 50, and more preferably of at
least 100. Examples of COX-2 inhibitors are provided in, but not
limited to, Table Nos. 1 and 2.
[0068] The referenced tables provided herein, provides
non-exhaustive examples of each subtype that may be used in
combinations and methods of the present invention
1TABLE 1 COX-2 Inhibitors Trade Cancer Compound Name Company Mode
of Action Reference Dosage Toxicity Indication lornoxicam Safem
Roche Cyclooxygenase Cynomolgus Holding inhibitor monkeys: AG 1-2
mg/kg/day orally for six weeks 1,5-Diphenyl-3- Fujisawa
Cyclooxygenase WO- substituted Phar- 2 inhibitor 09713755 pyrazoles
mceu- tical Co Ltd radicicol Scripps Tyrosine kinase WO- Research
inhibitor, 09625928; Insti- Cyclooxygenase Kwon et tute 2
modulator, al IL-1 (Cancer antagonist, TNF Res (1992) alpha 52
6296) antagonist N-benzyl-3- Merck & Cyclooxygenase US-
indoleacetic acids Co Inc inhibitor, 05510368 Anticancer
GB-02283745 Merck & Cyclooxygenase Co Inc 2 inhibitor TP-72
Dart- NO synthesis Cancer mouth inhibitor, Res 1998 Medical
Cyclooxygenase 58 4 717- School 2 inhibitor 723 Indene inhibitors
of American Cyclooxygenase WO- cox-2 Home 2 inhibito 09821195
Products Corp carbocyclic Bristol- Cyclooxygenase WO- Rat: >300
diarylmethylene Myers 2 inhibitor 09805643 mg/kg po derivatives
Squibb Co 1,2-Diarylindole Bristol- Cyclooxygenase WO- Myers 2
inhibitor 09805639 Squibb Co 1,2- Merck & Cyclooxygenase WO-
Bisarylcyclobutene Co Inc 2 inhibitor 09736863 derivatives Novel
stilbene Merck & Cyclooxygenase WO- derivatives as Co Inc 2
inhibitor 09728121 prodrug forms of the diphenylcyclopentenones
claimed in US- 05474995, WO- 09500501 and WO- 09518799.
2,4-Diphenylbutenoic Merck & WO- acid derivatives as Co Inc
09728120 prodrugs of COX-2 inhibitors claimed in US-05474995, WO-
09500501 and WO- 09518799. 1-(4-chlorobenzoyl)- A- Abbott
Cyclooxygenase 3-[4-(4-fluorophenyl) 183827.0 2 inhibitor
thiazol-2- ylmethyl]-5-methoxy- 2-methy lindole COX-2 Merck &
Cyclooxygenase WO Colon in- Co 2 inhibitor 9518799; cancer hibitor,
WO Merck 9608482; WO 9606840; WO 9621667; WO 9636623; WO 9744027
Sulfonamide substi- CS-179 Monsanto Cyclooxygenase tuted
diarylthiazole 2 inhibitor GR- Glaxo Cyclooxygenase Chronic 253035
Wellcome 2 inhibitor inflama- tory pain 4-(4-cyclohexyl-2- JTE-522
Japan Cyclooxygenase Pain methyloxazol-5-yl)- Tobacco 2 inhibitor
2- fluorobenzene- sulfonamide 5,6- L-768277 Merck &
Cyclooxygenase diarylthiazolo[3,2- Co 2 inhibitor B] [1,2,4]
triazolo L-783003 Merck & Cyclooxygenase Co 2 inhibitor MK-966
Merck & Cyclooxygenase 12.5-100 Co 2 inhibitor mg po
indometacin-derived Merck & Cyclooxygenase WO 200 indolalkanoic
acid Co 2 inhibitor 9637467-9 mg/kg/day 1-Methylsulfonyl-4-
Monsanto Cyclooxygenase WO [1,1-dimethyl-4-(4- 2 inhibitor 9530656;
fluorophenyl) WO cyclopenta-2,4- 9530652; dien-3-yl]benzene WO
9638418; WO 9638442 4,4-dimethyl-2- Merck & Cyclooxygenase
phenyl-3-[4- Co 2 inhibitor (methylsulfonyl) phenyl] cyclobutenone;
1,2- diarylcyclobutenes Chugai Cyclooxygenase WO 2 inhibitor
9730030 2-(4-methoxyphenyl)- Sankyo Cyclooxygenase EP
4-methyl-1-(4- 2 inhibitor 799823 sulfamoylphenyl) pyrrole; 1,2-
diphenylpyrrole derivatives tetrahydrofuranones Bristol-
Cyclooxygenase WO Myers 2 inhibitor 9737984 Squibb N-[5-(4- RWJ-
Johnson 5 Lipoxygenase fluoro)phenoxy] 63556 & inhibitor;
thiophene-2- Johnson Cyclooxygenase methanesulfonamide 2 inhibitor;
Leucotriene B4 antagonist 5(E)-(3,5-di-tert- S-2474 Shionogi
Prostaglandin EP butyl-4- E2 antagonist; 595546
hydroxy)benzylidene- Leucotriene B4 2-ethyl-1,2- antagonist;
isothiazolidine-1,1- Cyclooxygenase d ioxide 2 inhibitor SC-57666
Monsanto Cyclooxygenase 2 inhibitor 3-formylamino-7- T-614 Toyama
Cyclooxygenase DE methylsulfonylamino- 2 inhibitor; 3834204
6-phenoxy-4H-1- Interleukin 1b benzopyran-4-one antagonist;
Interleukin 6 antagonist Benzenesulfonamide, cele- Monsanto
Cyclooxygenase 4-(5-(4- coxib; 2 inhibitor methylphenyl)-3-
Celebrex; (trifluoromethyl)- SC- 1H-pyrazol-1-yl)- 58635; YM-177
2H-1,2- mel- Boeh- Cyclooxygenase US 15-30 Benzothiazine-3- oxicam;
ringer 2 inhibitor; 4233299 mg/day carboxamide, 4- Mobic; Ingel-
Prostaglandin hydroxy-2-methyl-N- Mobec; heim synthase (5-methyl-2-
Moricox; inhibitor thiazolyl)-, 1,1- Mobicox; dioxide- Movalis;
Methanesulfonamide, nim- Helsinn Cyclooxygenase US N-(4-nitro-2-
esulide 2 inhibitor; 3840597 phenoxyphenyl) Prostaglandin synthase
inhibitor Methanesulfonamide, nim- Poli Cyclooxygenase
N-(4-nitro-2- esulide, 2 inhibitor phenoxyphentyl) Poli valdecox
Monsanto COX-2 inhibitor US ib 5,633,272
[0069]
2TABLE 2 Preferred COX-2 Inhibitors Publication/issue/filing Dosage
of Preferred Patent Dates Oncology Indication Compounds US 5776967
A 980707 colorectal cancer WO 9821195 A1 980522 colorectal cancer
WO 9804527 A1 980205 colorectal cancer 0.01-100 mg/kg/day orally or
parenterally WO 9825896 A1 980618 US 5760068 A 980602 WO 9822101 A2
980528 colorectal cancer WO 9816227 A1 980423 antiangiogenic US
5719163 A 980217 epithelial cell neoplasia WO 9806708 A1 980219 WO
9738986 A 971023 US 5663180 A 970902 WO 9729776 A1 970821 WO
9729774 A1 970821 cancer 0.1-2000 (preferably 0.5- 500, especially
1-100) mg/kg/day orally, intravascularly, intraperitoneally,
subcutaneously, intramuscularly, or topically. WO 9729775 A1 970821
cancer 0.1-2000 (preferably 0.5- 500, especially 1-100) mg/kg/day
orally, intravascularly, intraperitoneally, subcutaneously,
intramuscularly, or topically. WO 9727181 A1 970731 WO 9714679 A2
970424 WO 9711704 A1 970403 US 5616601 A 970401 WO 9641645 A1
961227 WO 9641625 A1 961227 colorectal cancer 0.01-100 mg/kg/day
oral, topical or parenteral. WO 9641626 A1 961227 WO 9638442 A1
961205 WO 9638418 A1 961205 colorectal cancer 0.1-100 (preferably
0.1- 10) mg/kg/day, orally, injection, topically, or transdermally.
WO 9625405 A1 960822 WO 9624585 A1 960815 WO 9609293 A1 960328 WO
9603387 A1 960208 US 5739166 980414 colorectal cancer 0.01-100
(preferably 0.1- WO 9616934 A1 960606 10 mg/kg/day, orally, topical
or intramuscular WO 9603388 A1 960208 WO 9603392 A1 960208 WO
9530652 A1 951116 WO 9515316 A1 950608 WO 9515318 A1 950608 US
5393790 A 950228 US 5380738 950110 colorectal cancer 0.01-100
(pref. 0.1-50) WO 9427980 A1 941208 mg/kg/day, oral, parental, or
topical US 5719163 980217 colorectal cancer 0.01-100 (pref. 0.1-50)
WO 9427980 A1 941208 mg/kg/day, oral, parental, or topical. US
5420343 A 950530 US 5434178 950718 US 5466823 951114 US 5521207
960528 US 5563165 961008 US 5508426 960416 US 5504215 960402 US
5516907 960514 US 5510496 960423 US 5753688 980519 US 5753688
980519 US 5736579 980407 colorectal cancer WO 9521817 A1 950817
SOFRC 95/1107 960424 US 5668161 970916 US 5418254 950523 US 5576339
961119 colorectal cancer US 5672626 970930 US 5670510 970923 US
5686470 971111 colorectal cancer 0.01-100 (preferably 0.1- WO
9624584 A1 960815 10) mg/kg/day US 5580985 961203 0.01-100
(preferably 0.1- WO 9603385 A1 960208 10) mg/kg/day US 5756530
980526 0.01-100 (preferably 0.1- WO 9603385 A1 960208 10) mg/kg/day
US 5486534 A 960123 WO 9603385 A1 960208 US 5620999 970415
colorectal cancer 0.01-100 (preferably 0.5- WO 9603387 A1 960208
20) mg/kg/day, oral, intravascular, intraperitoneal, subcutaneous,
intramuscular, or topical US 08/765,865 970110 US 5696143 970912 WO
960923 A1 960328 US 5547975 960820 WO 9609304 A1 960328 US
08/809475 970609 US 5565432 961015 WO 9609304 A1 960328 US 5670532
970923 WO 9609304 A1 960323 US 5596008 970121 WO 9624585 A1 960815
US 08/809318 970320 US 08/849069 971117 US 08/387680 950213 US
08/894124 970811 US 08/702417 960814 US 08/801768 970218 US 5643933
970701 WO 9638442 A1 961205 US 08/952661 960420 US 08/945840 960531
US 08/822528 970324 US 08/541850 951010 US 08/540522 951010 PCT
US97/05497 970411 US 08/908554 970808 US 09/005610 980112 US
08/987356 971209 US 60/032688 961210 PCT US98/07677 980418 US
09/062537 980417 US 60/044485 970421 US 08/004/822 930115 US
08/464722 950624 US 08/425022 950413 US 08/425029 950419 US
08/424979 950419 US 08/969953 971125 US 5380738 950110 US 08/952156
971111 US 08/647911 960530 US 08/457902 950601 US 08/957345 971024
EPO 95909447.5 950207 US 08/776358 970124 US 08/237739 940504 US
08/894102 970808 EPO 95928164.3 950727 US 09/191493 980709 US
08/992327 971217 US 08/776090 970609 US 08/765865 970110 AT 9700165
A 980415 AU 9719132 A 970814 CA 2164559 AA 960610 DE 19518421 A1
961121 DE 19533643 A1 970313 0.01-1000 mg/day orally or
parenterally DE 19533644 A1 970313 0.01-1000 mg/day orally or
parenterally EP 714895 A1 960605 0.001-150 (preferably 5- 20)
mg/kg/day EP 799823 A1 971008 EP 832652 A1 980401 adenocarcinoma EP
846689 A1 980610 metastasis inhibitors EP 850894 A1 980701 EP
850895 A1 980701 FR 2751966 A1 980206 Oral or parenteral 0.1- 100
mg/kg/day. GB 2283745 A1 950517 GB 2294879 A1 960515 GB 2319772 A
980603 cancer 50 mg to 5 g/day DE 19753463 A1 980604 (preferably
100-500 mg/day in 1 to 3 doses) GB 2320715 A 980701 JP 08157361 A2
960618 JP 09048769 A2 970218 JP 09071656 A2 970318 JP 09071657 A2
970318 JP 09077664 A2 970325 JP 09194354 A2 970729 ulcerative
colitis JP 09221422 A2 970826 JP 10175861 A2 980630 metastasis
inhibitors US 5474995 A 951212 US 5510368 A 960423 0.1-140
mg/kg/day or 0.5- 7 g/patient, oral, topical, perenteral,
inhalation, rectal US 5604260 A 970218 US 5616458 A 970401 US
5633272 A 970527 US 5663195 A 970902 0.01-100 mg/kg/day; 0.5 mg-6
g/day US 5677318 A 971014 inhibitor of cellular neoplastic
transformations and metastatic tumor growth; treatment of
proliferative disorders, e.g., tumor angiogenesis US 5677318 A
971014 US 5681842 A 971028 US 5686460 A 971111 US 5733909 A 980331
US 5783597 A 980721 US 9413635 A1 940623 WO 9414977 A1 940707 WO
9420480 A1 940915 Inhibition of neoplastic 0.01-140 mg/kg/day
transformations and adminstered orally. metastatic tumor growth WO
9426731 A1 941124 WO 9500501 A2 950105 WO 9511883 A1 950504
colorectal cancer WO 9606840 A1 960307 WO 9608482 A1 960321 WO
9611676 A1 960425 0.01-140 mg/kg/day WO 9612483 A1 960502
inhibition of nitric oxide formation WO 9613483 A1 960509
Inhibition of neoplastic 0.01-140 mg/kg/day transformation and
metastatic tumor growth WO 9619462 A1 960627 0.01-1000 (preferably
0.1-300) mg/day p.o. or parenterally WO 9619462 A1 960627 WO
9619463 A1 960627 WO 9619463 A1 960627 0.1-1000 (preferably 1- 300)
mg/day p.o. or parenterally WO 9619469 A1 960627 WO 9621667 A1
969718 WO 9623786 A1 960808 osteosarcoma 0.01-140 mg/kg/day,
orally, rectal, injection, topical. WO 9624604 A1 960815 WO 9625405
A1 960822 WO 9625928 A1 960829 WO 9626921 A1 960906 WO 9631509 A1
961010 WO 9636617 A1 961121 colorectal cancer WO 9636623 A1 961121
WO 9637467 A1 961128 0.01-140 mg/kg/day, orally, topical,
parenteral, rectal or inhalation. WO 9637469 A1 961128 WO 9639144
A1 961212 WO 9640143 A1 961219 WO 9641626 A1 961227 colorectal
cancer WO 9703667 A1 970206 colonic adenomas; colonic
adenocarcinoma WO 9703953 A1 970206 0.01-1000 MG p.o or i.p. (oral,
parenteral rectal, topical or transdermal) WO 9709977 A1 970320 WO
9710840 A1 970327 WO 9711701 A1 970403 cancer WO 9711701 A1 970403
WO 9713755 A1 970417 cancer WO 9713767 A1 970417 WO 9714691 A1
970424 WO 9716435 A1 970509 WO 9725045 A1 970717 0.1-80 mg/kg/day
orally or parenterally WO 9725046 A1 970717 WO 9725047 A1 970717
0.1-80 mg/kg/day oral or parenteral WO 9725048 A1 970717 pulmonary
sarcoisosis 0.1-80 mg/kg/day oral or parenteral WO 9727181 A1
970731 colorectal cancer WO 9728120 A1 970807 WO 9728121 A1 970807
0.01-140 mg/kg/day WO 9730030 A1 970821 3-150 mg/hg p.o. or 1-50
mg/hg parenterally WO 9731631 A1 970904 WO 9734882 A1 970925
colorectal cancer WO 9736497 A2 971009 antineoplastic; prostate,
renal, colon, breast, or cervical cancer WO 9736863 A1 971009
0.01-140 mg/kg/day (oral, topical, rectal, parenteral, inhalation)
WO 9737984 A1 971016 Orally 300 mg/kg/day WO 9738686 A1 971023
regulation of COX-II expression WO 9740012 A1 971030 WO 9744027 A1
971127 Orally 2.5-250 mg/day (preferably 12.5-20 mg/day) WO 9744028
A1 971127 WO 9745420 A1 971204 WO 9746524 A1 971211 WO 9746532 A1
971211 0.08-15.0 mg/kg/day (preferably 0.16-3.0 mg/kg/day) WO
9800416 A1 980108 WO 9803484 A1 980129 Inhibit neoplastic Orally
0.01-140 mg/kg/day formation and metastic (preferably 0.5-7 tumor
growth mg/kg/day) WO 9805639 A1 980212 WO 9806715 A1 980219 WO
9807425 A1 980226 0.01-80 mg/kg/day oral or parenteral; topical
0.1- 150 mg/day in 1-4 doses. WO 9807714 A1 980226 WO 9811080 A1
980319 1-1000 mg/day (oral, rectal, topical); 0.1-500 mg/day
parenteral. WO 9815528 A1 980416 WO 9816227 A1 980423 WO 9817292 A1
980430 WO 9821195 A1 980522 tumor angiogenesis; colorectal cancers
WO 9822101 A2 980528 metastasis WO 9822104 A2 980528 WO 9822442 A2
980528 WO 9822457 A1 980528 WO 9824782 A2 980611 ZA 9704806 A
980325 colon cancer 0.1-500 mg/kg/day administered orally
WO98/57924 WO98/39330 WO98/41516 WO98/46594 WO98/47871 WO98/47890
WO99/18960 WO99/23087 WO99/24025 WO99/15503 WO99/14195 WO99/14194
WO99/05104 WO99/12930 WO99/10332 WO99/10331 WO99/11605 WO99/33796
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1995 WO 96/06840 07 Mar. 1996 WO 96/37468 28 Nov. 1996 WO 96/42941
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5,932,994 03 Aug. 1999
[0070] Preferred Combinations Generally
[0071] A preferred combination therapy consists essentially of a
COX-2 inhibitor in combination with a radiotherapeutic agent.
[0072] Examples of COX-2 inhibitors that may be used in the
combination therapy are provided in, but not limited to, Table No.
1. Preferred COX-2 inhibitors that may be used in the combination
therapy are shown in Table No. 2. The most preferred COX-2
inhibitors are selected from the group consisting of: 12345678
[0073] COX-2 Inhibitors
[0074] Specific COX-2 inhibitors are useful for the treatment of
cancer (WO98/16227) and in several animal models reduce
angiogenesis driven by various growth factors (WO98/22101).
Anti-angiogenesis was achieved with a COX-2 inhibitor in rats
implanted with bFGF, vascular endothelium growth factor (VEGF) or
carrageenan, proteins with well-known angiogenic properties.
(Masferrer, et al., 89.sup.th Annual Meeting of the American
Association for Cancer Research, March 1998.)
[0075] Dosage of COX-2 Inhibitors
[0076] Dosage levels of COX-2 inhibitors on the order of about 0.1
mg to about 10,000 mg of the active antiangiogenic ingredient
compound are useful in the treatment of the above conditions, with
preferred levels of about 1.0 mg to about 1,000 mg. The amount of
active ingredient that may be combined with other anticancer agents
to produce a single dosage form will vary depending upon the host
treated and the particular mode of administration.
[0077] It is understood, however, that a specific dose level for
any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
rate of excretion, drug combination, and the severity of the
particular disease being treated and form of administration.
[0078] Treatment dosages generally may be titrated to optimize
safety and efficacy. Typically, dosage-effect relationships from in
vitro initially can provide useful guidance on the proper doses for
patient administration. Studies in animal models also generally may
be used for guidance regarding effective dosages for treatment of
cancers in accordance with the present invention. In terms of
treatment protocols, it should be appreciated that the dosage to be
administered will depend on several factors, including the
particular agent that is administered, the route administered, the
condition of the particular patient, etc. Generally speaking, one
will desire to administer an amount of the compound that is
effective to achieve a serum level commensurate with the
concentrations found to be effective in vitro. Thus, where an
compound is found to demonstrate in vitro activity at, e.g., 10
.mu.M, one will desire to administer an amount of the drug that is
effective to provide about a 10 .mu.M concentration in vivo.
Determination of these parameters are well within the skill of the
art.
[0079] These considerations, as well as effective formulations and
administration procedures are well known in the art and are
described in standard textbooks.
[0080] Administration Regimen
[0081] Any effective treatment regimen can be utilized and readily
determined and repeated as necessary to effect treatment. In
clinical practice, the compositions containing a COX-2 inhibitor
alone or in combination with other therapeutic agents are
administered in specific cycles until a response is obtained.
[0082] For patients who initially present without advanced or
metastatic cancer, a COX-2 inhibitor in combination with radiation
therapy, is used 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 and inhibit
the growth of tumor cells from undetectable residual primary
tumor.
[0083] For patients who initially present with advanced or
metastatic cancer, a COX-2 inhibitor in combination with radiation
therapy 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.
[0084] 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.
[0085] Colorectal Cancer
[0086] The preferred combination therapy for the treatment of
colorectal cancer is surgery, followed by a regimen of one or more
chemotherapeutic agents, cycled over a one year time period. In the
treatment of colorectal cancer, radiation alone or in combination
with surgery and/or chemotherapeutic agents is often used.
Preferred chemotherapeutic agents include fluorouracil, and
Levamisole. Preferably, fluorouracil and Levamisole are used in
combination.
[0087] Prostate Cancer
[0088] Current therapies for prostate cancer focus upon reducing
levels of dihydrotestosterone to decrease or prevent growth of
prostate cancer. Radiation alone or in combination with surgery
and/or chemotherapeutic agents is often used.
[0089] Pancreas Cancer
[0090] Preferred combinations of therapy for the treatment of
non-metastatic adenocarcinoma include the use of 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); adjuvant radiation; and chemotherapy. For the
treatment of metastatic adenocarcinoma, the preferred chemotherapy
consists of 5-fluorouracil, followed weekly cisplatin therapy.
[0091] Lung Cancer
[0092] 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.
[0093] 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.
[0094] Non-Small Cell Lung Cancer
[0095] 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.
[0096] 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
[0097] 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 prefered 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.
[0098] 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.
[0099] 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 and chemotherapy, and the following
examples are the preferred treatment regimens and are generally
known by those skilled in the art and are provided for illustration
only and are not intended to limit the use of other combinations.
"Sequential" radiation therapy and chemotherapy refers to the
administration of chemotherapy and radiation therapy separately in
time in order to allow the separate administration of either
chemotherapy or radiation therapy. "Concomitant" radiation therapy
and chemotherapy refers to the administration of chemotherapy and
radiation therapy on the same day. Finally, "alternating" radiation
therapy and chemotherapy refers to the administration of radiation
therapy on the days in which chemotherapy would not have been
administered if it was given alone.
[0100] 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. (J.
Clin. Oncol. 1992, 10, 829-838).
[0101] Japanese Patent Kokai 5-163293 refers to 16-membered-ring
macrolide antibiotics 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.
[0102] WO 93/18652 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.
[0103] 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.
[0104] Tetragenesis, 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.
[0105] In addition, interleukins are known to have an antitumor
effect, but have not been reported to be effective against
non-small cell lung cancers.
[0106] Any 14- or 15-membered-ring macrolides have not been
reported to be effective against non-small cell lung cancers.
[0107] However, several chemotherapeutic agents have been shown to
be efficacious against NSCLC. Preferred chemotherapeutic agents
against NSCLC include etoposide, carboplatin, methotrexate,
5-fluorouracil, epirubicin, doxorubicin, and cyclophosphamide. The
most preferred chemotherapeutic agents active against NSCLC include
cisplatin, ifosfamide, mitomycin C, epirubicin, vinblastine, and
vindesine.
[0108] Other agents that are under investigation for use against
NSCLC include: camptothecins, a topoisomerase 1 inhibitor;
navelbine (vinorelbine), a microtubule assebly inhibitor; taxol,
inhibitor of normal mitotic activity; gemcitabine, a deoxycytidine
analogue; fotemustine, a nitrosourea compound; and edatrexate, a
antifol.
[0109] 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, Chest. 1991, 99: 1325; Bakowsk,
Cancer Treat. Rev. 1983, 10:159; Joss, Cancer Treat. Rev. 1984, 11:
205.
[0110] Small Cell Lung Cancer
[0111] Approximately 15 to 20 percent of all cases of lung cancer
reported worldwide is small cell lung cancer (SCLC). (Ihde, Cancer
1984, 54, 2722). 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.
[0112] The most preferred chemotherapeutic agents against SCLC
include vincristine, cisplatin, carboplatin, cyclophosphamide,
epirubicin (high dose), etoposide (VP-16) I.V., etoposide (VP-16)
oral, isofamide, teniposide (VM-26), and doxorubicin. Preferred
single-agents chemotherapeutic agents 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.
[0113] The poor results reported from single-agent chemotherapy has
led to use of combination chemotherapy.
[0114] Additionally, radiation therapy in conjunction with the
preferred combinations of angiogenesis inhibitors 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.
[0115] Breast Cancer
[0116] Today, among women in the United States, breast cancer
remains the most frequent diagnoses cancer. One in 8 women in the
United States 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.
[0117] Different chemotherapeutic agents are known in the 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).
[0118] In the treatment of locally advanced noninflammatory breast
cancer, a COX-2 inhibitor and radiation therapy can be used to
treat the disease in combination with other antiangiogenic agents,
or in combination with surgery, or with chemotherapeutic agents.
Preferred combinations of chemotherapeutic agents, and surgery that
can be used in combination with the radiation therapy and COX-2
inhibitors include, but are not limited to: 1) doxorubicin,
vincristine; 2) cyclophosphamide, doxorubicin, 5-flourouracil,
vincristine, prednisone; 3) cyclophosphamide, doxorubicin,
5-flourouracil, premarin, tamoxifen; 4) cyclophosphamide,
doxorubicin, 5-flourouracil, premarin, tamoxifen, mastectomy; 5)
mastectomy, levamisole; 6) mastectomy; and 7) mastecomy,
cyclophosphamide, doxorubicin, 5-fluorouracil, tamoxifen,
halotestin.
[0119] In the treatment of locally advanced inflammatory breast
cancer, COX-2 inhibitors and radiation therapy can be used to treat
the disease in combination with other antiangiogenic agents, or in
combination with surgery, or with chemotherapeutic agents.
Preferred combinations of chemotherapeutic agents, radiation
therapy and surgery that can be used in combination with the COX-2
inhibitors and radiation include, but or not limited to: 1)
cyclophosphamide, doxorubicin, 5-fluorouracil; 2) cyclophosphamide,
doxorubicin, 5-fluorouracil, mastectomy; 3) 5-flurouracil,
doxorubicin, clyclophosphamide, vincristine, prednisone,
mastectomy; 4) 5-flurouracil, doxorubicin, clyclophosphamide,
vincristine, mastectomy; 5) cyclophosphamide, doxorubicin,
5-fluorouracil, vincristine; 6) cyclophosphamide, doxorubicin,
5-fluorouracil, vincristine, mastectomy; 7) doxorubicin,
vincristine, methotrexate, followed by vincristine,
cyclophosphamide, 5-florouracil; 8) doxorubicin, vincristine,
cyclophosphamide, methotrexate, 5-florouracil, followed by
vincristine, cyclophosphamide, 5-florouracil; 9) surgery, followed
by cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,
tamoxifen, followed by cyclophosphamide, methotrexate,
5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine,
tamoxifen; 10) surgery, followed by cyclophosphamide, methotrexate,
5-fluorouracil, followed by cyclophosphamide, methotrexate,
5-fluorouracil, predinsone, tamoxifen, doxorubicin, vincristine,
tamoxifen; 11) surgery, followed by cyclophosphamide, methotrexate,
5-fluorouracil, predinsone, tamoxifen, followed by
cyclophosphamide, methotrexate, 5-fluorouracil, doxorubicin,
vincristine, tamoxifen; 12) surgery, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, predinsone, tamoxifen, doxorubicin,
vincristine; 13) surgery, followed by cyclophosphamide,
methotrexate, 5-fluorouracil, predinsone, tamoxifen, followed by
cyclophosphamide, methotrexate, 5-fluorouracil, predinsone,
tamoxifen, doxorubicin, vincristine, tamoxifen; 14) surgery,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
predinsone, tamoxifen, doxorubicin, vincristine; 15) surgery,
followed by cyclophosphamide, methotrexate, 5-fluorouracil,
predinsone, tamoxifen, followed by cyclophosphamide, methotrexate,
5-fluorouracil, doxorubicin, vincristine; 16) 5-florouracil,
doxorubicin, cyclophosphamide followed by mastectomy, followed by
5-florouracil, doxorubicin, cyclophosphamide.
[0120] In the treatment of metastatic breast cancer, radiation
therapy and COX-2 inhibitors are used to treat the disease in
combination with surgery, or with chemotherapeutic agents.
Preferred combinations of chemotherapeutic agents, and surgery that
can be used in combination with the radiation therapy and COX-2
inhibitors include, but are not limited to: 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.
[0121] Bladder Cancer
[0122] The classification of bladder cancer is divided into three
main classes: 1) superficial disease, 2) muscle-invasive disease,
and 3) metastatic disease.
[0123] 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.
[0124] 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.
[0125] In the treatment of superficial bladder cancer, COX-2
inhibitors and radiation therapy are used to treat the disease in
combination with surgery (TUR), and intravesical therapies.
[0126] Preferred combinations of chemotherapeutic agents are
selected from the group consisting of thiotepa (30 to 60 mg/day),
mitomycin C (20 to 60 mg/day), and doxorubicin (20 to 80
mg/day).
[0127] The preferred intravesicle immunotherapuetic agent that may
be used in the present invention is BCG. The preferred daily dose
ranges from 60 to 120 mg, depending on the strain of the live
attenuated tuberculosis organism used.
[0128] The 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.
[0129] In the treatment of muscle-invasive bladder cancer,
radiation therapy and COX-2 inhibitors can be used to treat the
disease in combination with other antiangiogenic agents, or in
combination with surgery (TUR), intravesical chemotherapy, and
radical cystectomy with pelvic lymph node dissection.
[0130] The preferred radiation dose 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.
[0131] The preferred combination of chemotherapeutic agents that
can be used in combination with radiation therapy and the COX-2
inhibitors is cisplatin, methotrexate, vinblastine.
[0132] 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.
[0133] In the treatment of metastatic bladder cancer, a combination
of radiation therapy and COX-2 inhibitors can be used to treat the
disease in combination with surgery, or with chemotherapeutic
agents.
[0134] Preferred combinations of chemotherapeutic agents include,
but are not limited to: 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.
[0135] Head and Neck Cancers
[0136] Head and neck cancer accounts for approximately 2% of new
cancer cases in the United States. Common intracranial neoplasms
include glioma, meningioma, neurinoma, and adenoma.
[0137] Preferred combinations that can be used along with a
combination of radiation therapy and a COX-2 inhibitor for the
treatment of malignant glioma include: 1) BCNU (carmustine); 2)
methyl CCNU (lomustine); 3) medrol; 4) procarbazine; 5) BCNU,
medrol; 6) misonidazole, BCNU; 7) streptozotocin; 8) BCNU,
procarbazine; 9) BCNU, hydroxyurea, procarbazine, VM-26; 10) BNCU,
5-flourouacil; 11) methyl CCNU, dacarbazine; 12) misonidazole,
BCNU; and 13) PCNJ. The preferred dose of radiation therapy is
about 5,500 to about 6,000 cGY. Preferred radiosensitizers include
misonidazole, intraarterial Budr and intravenous iododeoxyuridine
(IUdR).
[0138] Biological Evaluation
[0139] NFSA Tumor
[0140] The NFSA sarcoma is a nonimmunogenic and prostaglandin
producing tumor that spontaneously developed in C3Hf/Kam mice It
exhibits an increased radioresponse if Indomethacin is given prior
to tumor irradiation. The NFSA tumor is relatively radioresistant
and is strongly infiltrated by inflammatory mononuclear cells,
primarily macrophages which secrete factors that stimulate tumor
cell proliferation. Furthermore, this tumor produces a number of
prostaglandins, including prostaglandin E.sub.2 and prostaglandin
I.sub.2.
[0141] Solitary tumors were generated in the right hind legs of
mice by the injection of 3.times.10.sup.5 viable NFSA tumor cells.
Treatment with a COX-2 inhibitor (6 mg/kg body weight) or vehicle
(0.05% Tween 20 and 0.95% polyethylene glycol) given in the
drinking water was started when tumors were approximately 6 mm in
diameter and the treatment was continued for 10 consecutive days.
Water bottles were changed every 3 days. In some experiments, tumor
irradiation was performed 3-8 days after initiation of the
treatment with a COX-2 inhibitor. The end points of the treatment
were tumor growth delay (days) and TCD.sub.50 (tumor control dose
50, defined as the radiation dose yielding local tumor cure in 50%
of irradiated mice 120 days after irradiation). To obtain tumor
growth curves, three mutually orthogonal diameters of tumors were
measured daily with a vernier caliper, and the mean values were
calculated. In FIG. 1, which plots the growth of tumor treated with
vehicle (.smallcircle.) or COX-2 inhibitor (.circle-solid.), the
groups consisted of eight mice each, respectively. Treatment of
mice with a COX-2 inhibitor alone significantly inhibited tumor
growth.
[0142] Local tumor irradiation with single Y-ray doses of 30, 40,
or 50 Gy was given when these tumors reached 8 mm in diameter.
Irradiation to the tumor was delivered from a dual-source
.sup.137Cs irradiator at a dose rate of 6.31 Gy/minute. During
irradiation, unanesthetized mice were immobolized on a jig and the
tumor was centered in a circular radiation field 3 cm in diameter.
Regression and regrowth of tumors were followed at 1-3 day
intervals until the tumor diameter reached approximately 14 mm.
FIG. 2 plots the growth curves to illustrate the effect of a COX-2
inhibitor on tumor growth when combined with a radiation dose of 30
Gy. Day 0 designates the time of tumor irradiation; it should be
noted, however, that tumors in the groups receiving a COX-2
inhibitor reached the size of 8 mm (day 0) at a later time than
tumors treated with the vehicle. Groups consisted of five to eight
mice each. Two of eight mice in the COX-2 inhibitor only group died
of unknown causes. (.largecircle.=vehicle, .DELTA.=COX-2 inhibitor,
.circle-solid.30 Gy, and .tangle-solidup.=COX-2 inhibitor plus 30
Gy). Vertical bars represent 95% confidence intervals.
[0143] Tumor diameter doubling time, based on tumor growth from 6
to 12 mm in diameter, was increased from 7.3 days (95% confidence
interval [CI]=6.48.1 days) to 14.8 days (95% CI--11.5-18.1 days)
(P<0.0001). The effect of a COX-2 inhibitor was evident already
within 1 day from the start of the treatment.
[0144] The magnitude of tumor growth delay as a function of
radiation dose with or without treatment with a COX-2 inhibitor was
plotted (FIG. 3) to determine the enhancement of tumor response to
radiation. This requires that tumor growth delay after radiation be
expressed only as the absolute tumor growth delay, i.e., the time
in days for tumors treated with radiation to grow from 8 to 12 mm
in diameter minus the time in days for untreated tumors to-reach
the same size It also requires that the effect of the combined a
COX-2 inhibitor plus-radiation treatment be expressed as the
normalized tumor growth delay. Normalized tumor growth delay is
defined as the time for tumors treated with both a COX-2 inhibitor
and radiation to grow from 8 to 12 mm in diameter minus the time in
days for tumors treated with a COX-2 inhibitor alone to reach the
same size. Absolute tumor growth delay and normalized tumor growth
delay along with their 95% confidence intervals were plotted for
all three radiation doses used in this experiment (30, 40, and 50
Gy). The enhancement factor was 3.64 (95% confidence
interval=3.42-3.86), obtained by use of a likelihood analysis, to
fit the ratio of the slopes of the two lines. While no tumors were
cured by any of the three radiation doses given alone, tumors in
one of six, in two of six, and in one of eight animals were cured
when a COX-2 inhibitor treatment was combined with radiation
treatment at 30, 40, and 50 Gy, respectively. Two of eight mice in
the group that received the COX-2 inhibitor plus 40 Gy died of
unknown causes. The mice whose tumors were cured and the mice that
died were not included in tumor growth delay analysis.
[0145] The entire procedure for treatment with a COX-2 inhibitor
and local tumor irradiation was the same as that described in FIGS.
2-3. Here, the single doses of .gamma.-radiation ranged from 25 to
80 Gy. Mice were checked for the presence of tumor at the
irradiated site at 2- to 7-day intervals for up to 120 days, at
which time TCD values were calculated. TCD.sub.50 values (tumor
control dose 50 designates a radiation dose yielding 50% control
[regression] of local tumor) were computed by use of the logistic
model (Finney, Quartel response and the tolerance distribution.
Statistical methods in biological Assay, 2.sup.nd Ed., 1952) and
shown in FIG. 4 (radiation only and .tangle-solidup.--COX-2
inhibitor plus radiation. Horizontal bars represent 95% confidence
intervals, at the TCD.sub.50 dose level. Five of 60 mice that
received a COX-2 inhibitor plus radiation died of unknown causes.
The dead mice were excluded from TCD.sub.50 analysis. TCD.sub.50
assays contained 57 mice that received radiation only and 55 mice
that received a combination of the COX-2 inhibitor and
radiation.
[0146] A COX-2 inhibitor co-treatment increased the effect of tumor
irradiation, as shown by both tumor growth delay (FIGS. 2 and 3)
and tumor cure rate (FIG. 4). The growth delay after the combined
treatment was more than the sum of growth delays caused by either
irradiation alone or a COX-2 inhibitor alone (FIG. 2). Tumors in
control mice required 4.6 days (95% CI=3.9-5.4 days) to grow from 8
to 12 mm in diameter. Mice treated with a COX-2 inhibitor required
7.1 days (95% CI=5.0-9.2 days) (P=0.003), mice treated with 30 Gy
required 13.6 days (95% CI 10.5-16.7 days), and mice treated with
both agents required 43.5 days (95% CI=30.8-56.2 days) (P=0.001
compared with radiation-only group). The efficacy of irradiation
was enhanced by a factor of 3.64 (95% CI=3.42-3.86), determined
from the curves in FIG. 3, which plot the magnitude of tumor growth
delay as a function of radiation dose with or without treatment
with a COX-2 inhibitor. This compound also greatly enhanced the
tumor cure rate after irradiation (FIG. 4). The TCD.sub.50 value
was reduced from 69.2 Gy (95% CI=65.7-72.7 GY) in the
irradiation-only group to 39.2 Gy (95% CI=31.1-44.6 Gy) in the
combination-treatment group. The enhancement factor was 1.77 (95%
CI=1.51-1,99). obtained by dividing the TCD.sub.50 value of the
radiation-alone group by the combination-treatment group. The 95%
CI's were obtained by use of Fieller's theorem (Heron, J. Statist.
Comput. Simul., 1975, 3, 265-74).
[0147] A COX-2 inhibitor dramatically enhanced the tumor response
to radiation, as evidenced by the increase in tumor growth delay
and the augmentation of tumor curability. The enhancement factors
were 3.64 and 1,77, respectively, greater than the enhancement
factors of 1.4 and 1.26 for radiation-indomethacin and radiation
alone, respectively.
[0148] All documents referenced herein are incorporated by
reference.
[0149] Although this invention has been described with respect to
specific embodiments, the details of these embodiments are not to
be construed as limitations.
* * * * *