U.S. patent application number 10/559690 was filed with the patent office on 2007-06-21 for method for treating cancer patients undergoing chemotherapy.
Invention is credited to Shalom Z. Hirschman.
Application Number | 20070141044 10/559690 |
Document ID | / |
Family ID | 34215781 |
Filed Date | 2007-06-21 |
United States Patent
Application |
20070141044 |
Kind Code |
A1 |
Hirschman; Shalom Z. |
June 21, 2007 |
Method for treating cancer patients undergoing chemotherapy
Abstract
A method for treating cancer patients undergoing
chemotherapeutic treatments by administering Product R, a
peptide-nucleic acid preparation, is disclosed.
Inventors: |
Hirschman; Shalom Z.;
(Riverdale, NY) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Family ID: |
34215781 |
Appl. No.: |
10/559690 |
Filed: |
June 4, 2004 |
PCT Filed: |
June 4, 2004 |
PCT NO: |
PCT/US04/17762 |
371 Date: |
July 21, 2006 |
Current U.S.
Class: |
424/115 ;
514/19.3; 514/19.6 |
Current CPC
Class: |
A61P 7/06 20180101; A61K
38/01 20130101; A61P 43/00 20180101; A61K 31/00 20130101; A61K
45/06 20130101; A61K 31/7105 20130101; A61P 7/00 20180101; A61P
35/00 20180101; A61K 38/012 20130101; A61K 31/7105 20130101; A61K
2300/00 20130101; A61K 38/01 20130101; A61K 2300/00 20130101; A61K
38/012 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/115 ;
514/007 |
International
Class: |
A61K 38/16 20060101
A61K038/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 5, 2003 |
US |
10456668 |
Claims
1. A method of maintaining or increasing the number of white blood
cells in a cancer patient undergoing chemotherapeutic treatment for
cancer, comprising administering to said patient an effective
treatment amount of Product R.
2. The method of claim 1 in which said cancer patient does not have
basal cell carcinoma or a cancer of a lymphocytic cell.
3. The method of claim 1 or 2 in which said administering is not
subcutaneous, intralesional, topical or by injection.
4. The method of claim 1 in which said administering to said
patient is parenterally and said Product R is in a sterile
injectable formulation.
5. The method of claim 4 in which said cancer patient does not have
basal cell carcinoma or a cancer of a lymphocytic cell.
6. The method of claim 1 in which an effective treatment amount of
Product R is in a range from about 5 microliters to about 40
microliters per kilogram of body weight per day in a sterile
formulation.
7. The method of claim 1 in which an effective treatment amount of
Product R is in a range from about 10 microliters to about 25
microliters per kilogram of body weight per day in a sterile
formulation.
8. The method of claim 1 in which an effective treatment amount of
Product R is about 30 microliters per kilogram of body weight per
day in a sterile injectable formulation for about one week,
followed by about 15 microliters per kilogram of body weight per
day in a sterile formulation.
9. A method of maintaining or increasing the number of platelets in
the blood in a cancer patient undergoing chemotherapeutic treatment
for cancer, comprising administering to said patient an effective
treatment amount of Product R.
10. The method of claim 9 in which said cancer patient does not
have basal cell carcinoma or a cancer of a lymphocytic cell.
11. The method of claim 9 or 10 in which said administering is not
subcutaneous, intralesional, topical or by injection.
12. The method of claim 9 in which said administering to said
patient is parenterally and said Product R is in a sterile
injectable formulation.
13. The method of claim 12 in which said cancer patient does not
have basal cell carcinoma or a cancer of a lymphocytic cell.
14. The method of claim 9 in which an effective treatment amount of
Product R is in a range from about 5 microliters to about 40
microliters per kilogram of body weight per day in a sterile
formulation.
15. The method of claim 9 in which an effective treatment amount of
Product R is in a range from about 10 microliters to about 25
microliters per kilogram of body weight per day in a sterile
formulation.
16. The method of claim 9 in which an effective treatment amount of
Product R is about 30 microliters per kilogram of body weight per
day in a sterile injectable formulation for about one week,
followed by about 15 microliters per kilogram of body weight per
day in a sterile formulation.
17. A method of reducing gastric-intestinal toxicity in a cancer
patient resulting from an anti-cancer chemotherapeutic agent
comprising administering to said patient an effective treatment
amount of Product R.
18. The method of claim 17 in which said cancer patient does not
have basal cell carcinoma or a cancer of a lymphocytic cell.
19. The method of claim 17 or 18 in which said administering is not
subcutaneous, intralesional, topical or by injection.
20. The method of claim 17 in which said administering to said
patient is parenterally and said Product R is in a sterile
injectable formulation.
21. The method of claim 20 in which said cancer patient does not
have basal cell carcinoma or a cancer of a lymphocytic cell.
22. The method of claim 17 in which an effective treatment amount
of Product R is in a range from about 5 microliters to about 40
microliters per kilogram of body weight per day in a sterile
formulation.
23. The method of claim 17 in which an effective treatment amount
of Product R is in a range from about 10 microliters to about 25
microliters per kilogram of body weight per day in a sterile
formulation.
24. The method of claim 17 in which an effective treatment amount
of Product R is about 30 microliters per kilogram of body weight
per day in a sterile injectable formulation for about one week,
followed by about 15 microliters per kilogram of body weight per
day in a sterile formulation.
25. A pharmaceutical composition comprising an effective treatment
amount of Product R, an anti-cancer chemotherapeutic agent, and a
pharmaceutically acceptable carrier
26. A kit comprising a first container which contains an effective
treatment amount of Product R; and a second container which
contains an anti-cancer chemotherapeutic agent.
27. The kit of claim 26 further comprising a needle or syringe.
Description
1. FIELD OF THE INVENTION
[0001] The present invention relates to a method for using Product
R, a peptide-nucleic acid composition, to treat cancer patients
undergoing chemotherapeutic treatments.
2. BACKGROUND OF THE INVENTION
[0002] Malignant, or cancerous, tumors are defined by their
invasion of local tissue and their ability to spread or metastasize
to other parts of the body. The incidence of such tumors is high;
it is the second leading cause of death in both children and
adults. A malignant tumor, by definition, always kills (unless
treated) because of its invasive and metastatic characteristics.
The tumor grows locally by encroachment into the normal tissues
surrounding it. The tumor spreads to distant sites by the off of
malignant cells. These cells then move through the blood and
lymphatic systems, attach themselves more or less at a remote site,
and begin to grow as new colonies.
[0003] The factors controlling tumor growth are poorly understood.
Tumors in laboratory animals may be transplanted to a second host
using only a single tumor cell. This facility suggests that only
one normal cell need become transformed (cancerous) for tumor
growth to begin. It is thought, however, that many transformed
cells die or remain latent or dormant for extended periods before
successful tumor growth is established. Tumors have been
experimentally induced in animals by chemical, physical, and viral
agents, and by radiation and chronic irritation.
[0004] Immunological reactions can destroy neoplastic (potentially
malignant) cells in vivo, and the accumulation of macrophages
within a tumor can lead to its destruction. Cytotoxic T
lymphocytes, natural killer (NK) cells, and activated macrophages
can kill tumor cells in vitro. These observations suggest that the
immune system provides some resistance against the development and
spread of cancer, a contention strengthened by increased incidence
of spontaneous tumors in individuals with congenital or acquired
immune deficiency diseases.
[0005] Conventional treatment regimens for tumors include radiation
and drugs or a combination of both. All of the conventional
anti-cancer drugs are highly toxic and tend to make patients quite
ill while undergoing treatment. Vigorous therapy is based on the
premise that unless every cancerous cell is destroyed, the residual
cells will multiply and cause a relapse.
[0006] Most of the conventional chemotherapeutic drugs that are
being used in tumor therapy do not specifically kill tumor cells.
Reliance is placed on the fact that, in most cancers, the cancerous
cells grow faster than normal cells and will therefore utilize more
of the toxic chemotherapeutic drug thereby specifically killing the
cancer cell. Chemotherapy treatment is given either in a single or
in several large doses or, more commonly, it is given in small
doses 1 to 4 times a day over variable times from weeks to months.
There is a large number of cytotoxic agents used to treat cancer
and the mechanisms of the cytotoxic effects of each agent is
frequently not known or only partially known. Administration of the
conventional chemotherapeutic drugs requires careful attention to
the amount and concentration of the drug or combination of drugs so
that the cancer cells will be killed but normal cells will survive.
For this reason, it is difficult to kill all cancerous cells by
conventional chemotherapy. The successful use of chemotherapeutic
agents to treat cancer depends upon the differential killing effect
of the agent on cancer cells compared to effects on normal
tissues.
[0007] The effects of chemotherapeutic agents on normal tissues are
referred to as side-effects of cancer treatment. The immediate side
effects (minutes to a few hours) of chemotherapy may include
dizziness, nausea, vomiting, and diarrhea. These side effects are
uncomfortable but, in themselves, are not life-threatening. Cell
killing or damage within normal tissues that occurs from days to
weeks after a commencement of a course of chemotherapy may result
in uncomfortable and/or life threatening side effects. Among these
effects are hair loss, hearing loss, sterility, damage to the
mucosal epithelium of the gastrointestinal tract (namely, GI
toxicity), damage to the oral mucosa, esophagus, small and large
intestines, kidney damage, skin damage, cardiac damage, killing and
suppression of the white blood cells which can lead to infection,
reduction of platelets in the blood and killing of hematopoietic
blood forming cells. Many of these side effects are related to
tissues and organ systems that have a high number of dividing cells
(proliferative cells). Some of these side effects are non-life
threatening; however, a reduction or prevention of these effects
could have a beneficial effect on cancer patients or make it
possible to administer a higher dose of the chemotherapeutic agent
while minimizing damage or death of cells in normal tissue.
[0008] Reticulose.RTM. emerged as an antiviral product in the
1930's. While it was originally believed to be a product composed
of peptone, peptides and nucleic acids, the precise composition
remains unidentified. A method for preparing Reticulose.RTM. is
provided in U.S. Pat. No. 5,849,196, herein incorporated by
reference in its entirety. Nevertheless, Reticulose.RTM. has
demonstrated an ability to inhibit rapidly the course of several
viral diseases. It is nontoxic, miscible with tissue fluids and
blood sera and free from anaphylactogenic properties.
[0009] As taught by U.S. Pat. No. 5,849,196, the components over 15
KDa of the conventional composition of Reticulose.RTM. are more
effective in treating viral diseases such as HIV, influenza virus,
herpes simplex virus, etc. while the components in a range of
approximately 1 to 15 KDa function as phagocytosis inhibitors.
[0010] Reticulose.RTM. suffers from several disadvantages: 1) the
method of preparation does not ensure that each preparation
produces the finished components in the same ratio, i.e., the final
product is not reproducible; 2) the conventional method of
preparation produces a wide range of the finished components, which
makes the quality control of the preparation extremely difficult,
if possible, because too many parameters need to be determined; 3)
the presence of the higher molecular weight components, such as 25
KDa component, essentially peptides, increases the risk of
hypersensitivity or immune reaction and renders the product less
stable. Therefore, it is desirable to have a product devoid of the
deficiencies of conventional Reticulose.RTM. while maintaining its
therapeutic properties.
[0011] U.S. Pat. Nos. 6,303,153 and 6,528,098, both of which are
herein incorporated by reference in their entireties, disclose the
preparation of Product R, a composition derived from the same
starting materials as used in preparing Reticulose.RTM., but
distinct from Reticulose.RTM.. For example, material greater than
14 kDa molecular weight is removed when preparing Product R.
[0012] Insofar as the applicant knows, Product R has never been
used, nor suggested for treating cancer patients undergoing
chemotherapeutic treatments. It is now discovered that Product R
produces an unexpected result when administered to patients
undergoing chemotherapeutic treatments.
3. SUMMARY OF THE INVENTION
[0013] An object of this invention therefore is to provide a method
for treating cancer patients taking chemotherapeutic treatments,
which reduces the side effects of chemotherapeutic agents on the
cancer patients, and/or stimulates the immune system of the cancer
patients, by administering to the patients Product R, an antiviral
agent composed of peptides and nucleic acids.
[0014] The present invention encompasses methods of maintaining or
increasing the number of white blood cells in a cancer patient
undergoing chemotherapeutic treatment, comprising administering to
said patient an effective treatment amount of Product R. In certain
embodiments, the cancer patient does not have basal cell carcinoma
or cancer of a lymphocytic cell. In certain embodiments,
administering is not subcutaneous, intralesional, topical or by
injection. In a preferred embodiment, Product R is administered
parenterally in a sterile injectable formulation. In certain
embodiments, the effective treatment amount of Product R is in a
range from about 5 microliters to about 40 microliters per kilogram
of body weight per day, or from about 10 microliters to about 25
microliters per kilogram of body weight per day, in a sterile
formulation. In yet another embodiment, an effective treatment
amount of Product R is about 30 microliters per kilogram of body
weight per day in a sterile formulation for about one week,
followed by about 15 microliters per kilogram of body weight per
day in a sterile formulation.
[0015] The present invention also encompasses methods of
maintaining or increasing the number of platelets in the blood in a
cancer patient undergoing chemotherapeutic treatments, comprising
administering to said patient an effective treatment amount of
Product R. In certain embodiments, the cancer patient does not have
basal cell carcinoma or cancer of a lymphocytic cell. In certain
embodiments, administering is not subcutaneous, intralesional,
topical or by injection. In a preferred embodiment, Product R is
administered parenterally in a sterile injectable formulation. In
certain embodiments, the effective treatment amount of Product R is
in a range from about 5 microliters to about 40 microliters per
kilogram of body weight per day, or from about 10 microliters to
about 25 microliters per kilogram of body weight per day, in a
sterile formulation. In yet another embodiment, an effective
treatment amount of Product R is about 30 microliters per kilogram
of body weight per day in a sterile formulation for about one week,
followed by about 15 microliters per kilogram of body weight per
day in a sterile formulation.
[0016] The present invention also encompasses methods of reducing
gastric-intestinal toxicity in a cancer patient resulting from a
chemotherapeutic agent, comprising administering to said patient an
effective treatment amount of Product R. In certain embodiments,
the cancer patient does not have basal cell carcinoma or cancer of
a lymphocytic cell. In certain embodiments, administering is not
subcutaneous, intralesional, topical or by injection. In a
preferred embodiment, Product R is administered parenterally in an
sterile injectable formulation. In certain embodiments, the
effective treatment amount of Product R is in a range from about 5
microliters to about 40 microliters per kilogram of body weight per
day, or from about 10 microliters to about 25 microliters per
kilogram of body weight per day, in a sterile formulation. In yet
another embodiment, an effective treatment amount of Product R is
about 30 microliters per kilogram of body weight per day in a
sterile formulation for about one week, followed by about 15
microliters per kilogram of body weight per day in a sterile
formulation.
[0017] In specific embodiments, the patient has been administered
an anti-cancer chemotherapeutic agent prior to said step of
administering Product R.
[0018] The present invention further encompasses pharmaceutical
compositions comprising an effective treatment amount of Product R,
a chemotherapeutic agent, and a pharmaceutically acceptable
carrier.
[0019] The present invention further encompasses kits comprising a
first container which contains a unit dosage form of Product R and
a second container which contains a chemotherapeutic agent. In
certain embodiments, the kit also comprises a needle or
syringe.
4. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
[0020] The present invention provides methods and compositions for
treating with Product R cancer patients undergoing chemotherapy.
The therapeutic methods of the invention are based on reducing the
side effects of chemotherapeutic agents and/or eliciting an immune
response in a subject in whom the treatment of cancer is desired,
and who has been administered or will be administered a
chemotherapeutic agent.
[0021] As used herein, "about" entails normal experimental
variation.
[0022] A cancer of a lymphocytic cell includes, but is not limited
to, acute lymphocytic leukemia, chronic lymphocytic leukemia,
Hodgkin's disease and non-Hodgkin's lymphoma.
[0023] 4.1 Product R
[0024] Product R, a therapeutic composition for treating viral
infections and stimulating the immune system, comprises nucleotides
and peptides that have molecular weights not more than 14 KDa and
substantially not more than 8 KDa The composition has a light
absorption spectrum with typical absorption ratios of 1.998
(.+-.10%) at 260 nm/280 nm and 1.359 (.+-.10%) at 260 nm/230
nm.
[0025] Product R was used as a synonym of Reticulose.RTM. in some
literature. For the purpose of the present application, Product R
and Reticulose.RTM. represent two distinct products.
[0026] Generally, Product R is prepared according to the following
manner.
[0027] First, the starting materials casein, beef peptone, RNA,
bovine serum albumin (BSA), and sodium hydroxide are suspended in
proportions of, by weight, 35-50% (casein), 15-40% (beef peptone),
10-25% (RNA), 1-10% (BSA) and 5-25% (sodium hydroxide) in an
appropriate volume of distilled water. All starting materials are
generally available or otherwise can be readily prepared by a
person of ordinary skill in the art. While any RNA is suitable for
the intended purpose of the present invention, plant RNA is
preferred and yeast RNA is the most preferred. The ratio of total
proteins versus the volume of distilled water is generally about
1.5-2.5 to about 100 by weight, preferably about 2.2 to about 100
by weight. This means that every 1.5-2.5 grams of the total
proteins are suspended in about 100 milliliters of distilled
water.
[0028] The suspension as prepared above is then autoclaved at a
pressure of approximately 5-15 lbs., preferably 8-10 lbs. under an
elevated temperature in a range, for example, from about
150.degree.-300.degree. F., preferably from about
200.degree.-230.degree. F., over a period of approximately 2-10
hours, preferably more than 3 hours. As known to a person of
ordinary skill in the art, under such conditions RNA may be
completely hydrolyzed into nucleotides. After autoclaving, the
solution is cooled down to room temperature, and then allowed to
stay at a temperature of 3.degree. to 8.degree. C. for at least 12
hours to precipitate insoluble elements. Alternatively, the cooled
solution may be centrifuged at a temperature below 8.degree. C. to
remove the precipitates.
[0029] The resulting solution is then filtered through a 2 micron
and a 0.45 micron filters under an inert gas such as nitrogen or
argon at a pressure of about 1-6 psi. In a similar manner the
solution is filtered again through a pyrogen retention filter,
preferably 0.2 micron.
[0030] After the above filtration, the solution may be cooled at 3
to 8.degree. C. again for at least about 12 hours and filtered
again in the same way as described above.
[0031] The resulting filtrate is then assayed for total nitrogen
content using methods known to a person of ordinary skill in the
art such as Kjeldahl method (Kjeldahl, Z. 1983, Anal. Chem., Vol.
22:366), and its improvements. Based on the assay, the filtrate is
then diluted with chilled distilled water to an appropriate volume
having a preferred total nitrogen content ranging from 165 to 210
mg/ml.
[0032] The pH of the diluted solution is then adjusted with HCl to
a physiologically acceptable pH, preferably to about 7.3 to 7.6,
after which the diluted solution is filtered again through a 0.2
micron filter under an inert gas as described above.
[0033] Product R so produced contains essentially nucleotides,
nucleosides and free nucleic acid bases of low molecular weights
from a complete hydrolysis of RNA and small peptides from partial
hydrolysis of the proteins. It is possible that the base hydrolysis
of the proteins also produces free amino acids.
[0034] It is understood that the use of a filtration technique is
essentially to remove bacteria or other particles having similar
size to or larger size than bacteria. Thus, any filter regardless
of its manufacturer or material from which it is made is suitable
for the intended purpose. All filters used in the present process
are widely available to a person of ordinary skill in the art.
[0035] The final filtrate is then filled and sealed into
appropriate vials, such as 2 ml or 10 ml glass vials under an inert
gas. The filled vials are autoclaved for final sterilization, after
which they are ready for use.
[0036] An analysis of the composition of Product R reveals that
Product R contains two major components, which are exhibited as two
bands having molecular weights of 5.2 kDa and 4.3 kDa on a
SDS-polyacrymide gel electrophoresis, namely peptide-A and
peptide-B, respectively. Peptide-A is a novel single peptide and
peptide-B comprises a single peptide covalently bound to an
oligonucleotide. Peptide-A and peptide-B are present in the Product
R composition in an approximately equal amount and the total amount
of these two peptides is about 4.8-5.3 mg/ml, determined by a Lowry
protein assay.
[0037] The sequence of peptide A is:
KVLPVPQKAVPYPQRDMPIQAFLLYQEPVLG (SEQ ID NO. 1). The sequence of
peptide B is: GEIPDAGGRIVDYYVGFSDSV (SEQ ID NO. 2). Product R also
comprises nucleosides, nucleoside diphosphates and nucleoside
monophosphates.
[0038] The physical, chemical and biological properties of Product
R are further described in U.S. Pat. Nos. 6,303,153 and 6,528,098,
the contents of which are incorporated by reference in their
entirety.
[0039] 4.2 Target Cancers
[0040] The methods of the invention encompass the use of Product R
to treat patients undergoing therapy with chemotherapeutic agents.
In specific embodiments, this combination therapy can be used to
prevent the recurrence of cancer, inhibit metastasis, or inhibit
the growth and/or spread of cancer or metastasis.
[0041] Product R can be used to treat patients undergoing or that
will undergo chemotherapy for the types of cancers that include,
but are not limited to human sarcomas and carcinomas, e.g.,
fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic
sarcoma, chordoma, angiosarcoma, endotheliosarcoma,
lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma,
mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma,
colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer,
prostate cancer, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma,
papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,
medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma,
hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal
carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung
carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial
carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma,
ependymoma, pinealoma, hemangioblastoma, acoustic neuroma,
oligodendroglioma, meningioma, melanoma, neuroblastoma,
retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and
acute myelocytic leukemia (myeloblastic, promyelocytic,
myelomonocytic, monocytic and erythroleukemia); chronic leukemia
(chronic myelocytic (granulocytic) leukemia and chronic lymphocytic
leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and
non-Hodgkin's disease), multiple myeloma, Waldenstrom's
macroglobulinemia, and heavy chain disease.
[0042] In general, Product R is administered to a subject
undergoing chemotherapy with one or more anti-cancer agents. An
anti-cancer agent refers to any molecule or compound that assists
in the treatment of tumors or cancer. Such anti-cancer agents are
well known to those of skill in the art, and include, but are not
limited to, the following categories and specific compounds:
alkylating agents, antimetabolite agents, anti-tumor antibiotics,
vinca alkaloid and epidophyllotoxin agents, nitrosoureas,
synthetics, and hormonal therapeutic biologics.
[0043] Such alkylating agents may include, but are not limited to,
nitrogen mustard, chlorambucil, cyclophosphamide (cytoxan),
ifosfamide, melphalan, thiptepa and busulfan.
[0044] Antimetabolites can include, but are not limited to,
methotrexate, 5-fluorouracil, cytosine arabinoside (ara-C),
5-azacytidine, 6-mercaptopurine, 6-thioguanine, and fludarabine
phosphate. Antitumor antibiotics may include but are not limited to
doxorubicin (adriamycin), daunorubicin, dactinomycin, bleomycin,
mitomycin C, plicamycin, idarubicin, and mitoxantrone. Vinca
alkaloids and epipodophyllotoxins may include, but are not limited
to vincristine, vinblastine, vindesine, etoposide, and
teniposide.
[0045] Nitrosoureas include carmustine, lomustine, semustine and
streptozocin. Synthetics can include, but are not limited to
Dacrabazine, hexamethylmelamine, hydroxyurea, mitotane procabazine,
cisplatin, cisplatinum and carboplatin.
[0046] Hormonal therapeutics can include, but are not limited to
corticosteriods (cortisone acetate, hydrocortisone, prednisone,
prednisolone, methyl prednisolone and dexamethasone), estrogens,
(diethylstibesterol, estradiol, esterified estrogens, conjugated
estrogen, chlorotiasnene), progestins (medroxyprogesterone acetate,
hydroxy progesterone caproate, megestrol acetate), antiestrogens
(tamoxifen), aromastase inhibitors (aminoglutethimide), androgens
(testosterone propionate, methyltestosterone, fluoxymesterone,
testolactone), antiandrogens (flutamide), LHRH analogues
(leuprolide acetate), and endocrines for prostate cancer
(ketoconazole).
[0047] According to the invention, Product R can be administered
prior to, subsequently, or concurrently with anti-cancer agent(s),
for the treatment of cancer. Depending on the type of cancer, the
subject's history and condition, and the anti-cancer agent(s) of
choice, the use of the Product R can be coordinated with the dosage
and timing of chemotherapy.
[0048] Product R may also be used in therapy in conjunction with
other medicaments including corticosteroid, gamma globulin,
glucose, or vitamins, antiviral agents such as interferon or
interleukin, etc.
[0049] 4.3 Dosage and Administration
[0050] The individual or subject in whom treatment of an cancer is
desired is an animal, preferably a mammal, a non-human animal or
primate, and most preferably human. The term "animal" as used
herein includes but is not limited to companion animals, such as
cats and dogs; zoo animals; wild animals, including deers, foxes
and racoons; farm animals, livestock and fowl, including horses,
cattle, sheep, pigs, turkeys, ducks, and chickens, as well as any
rodents.
[0051] For the patients having side effects of chemotherapeutic
agents or suppressed immune systems caused by chemotherapeutic
agents such as, for example, 6-mercaptopurine, adriamycin,
bleomycin, cytoxan, chlorambucil, methotrexate, vincristine,
5-fluorouracil, or cisplatinum, whether chemotherapeutic agents are
employed individually or in any combination, a suitable effective
dose of Product R generally will be in the range of from about 5
microliters to about 40 microliters per kilogram of body weight per
day, preferably in the range of about 10 microliters to about 25
microliters per kilogram of body weight per day. Most preferably
Product R is administered in an amount of about 30 microliters per
kilogram of body weight per day for about one week, followed by
about 15 microliters per kilogram of body weight per day in a
sterile injectable formulation. The desired dose may be
administered as two, three or more sub-doses at appropriate
intervals, generally equally spread in time, throughout the day.
Preferably, the full daily dose is administered in one
administration.
[0052] Typical routes of administration for Product R may include,
without limitation, oral, topical, parenteral, sublingual, rectal,
vaginal, ocular, and intranasal. Parenteral administration includes
subcutaneous injections, intravenous, intramuscular,
intraperitoneal, intrapleural, intrasternal injection or infusion
techniques. In a preferred embodiment, Product R may be
administered by any suitable injection route including, but not
limited to intravenously, intraperitoneally, subcutaneously,
intramuscularly, and intradermally, etc. Preferably, the
compositions are administered parenterally, most preferably
intravenously. The presently preferred route of administration is
intramuscularly. It will be appreciated that the preferred route
may vary with, for example, the condition and age of the
recipient.
[0053] The efficacy of Product R can be assessed by the maintenance
or improvement of white blood cell counts, platelet production, or
reduction of gastrointestinal toxicity using standard methods well
known to one of ordinary skill in the art.
[0054] 4.4 Pharmaceutical Formulations
[0055] While it is possible for Product R to be administered as
part of a pharmaceutical formulation, it is preferable to present
it alone, although it may be administered at about the same time as
one or more other pharmaceuticals are independently administered.
If Product R is administered as part of a pharmaceutical
formulation, the formulations of the present invention comprise at
least one administered ingredient, i.e. Product R, as above
defined, together with one or more acceptable carriers thereof and
optionally other therapeutic ingredients. The carrier(s) must be
"acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0056] The formulations may conveniently be presented in unit-dose
or multi-dose containers, e.g. sealed ampules and vials.
[0057] Preferred unit dosage formulations are those containing a
daily dose or unit, daily sub-dose, or an appropriate fraction of
the administered ingredient.
[0058] The compositions of the invention can be in the form of a
solid, liquid or gas (aerosol). Pharmaceutical compositions of the
invention can be formulated so as to allow a compound of the
invention to be bioavailable upon administration of the composition
to a subject. Compositions can take the form of one or more dosage
units, where for example, a tablet can be a single dosage unit, and
a container of a compound of the invention in aerosol form can hold
a plurality of dosage units. A syringe containing a unit dose of
Product R is also provided.
[0059] 4.5 Kits
[0060] The invention also provides kits for carrying out the
methods and/or therapeutic regimens of the invention.
[0061] In one embodiment, such kits comprise in one or more
containers, Product R.
[0062] In another embodiment, such kits comprise in one or more
containers therapeutically or prophylactically effective amounts of
Product R in pharmaceutically acceptable form.
[0063] Product R in a container of a kit of the invention may be in
the form of a pharmaceutically acceptable solution, e.g., in
combination with sterile saline, dextrose solution, or buffered
solution, or other pharmaceutically acceptable sterile fluid.
Alternatively, Product R may be lyophilized or desiccated; in this
instance, the kit optionally further comprises in a container a
pharmaceutically acceptable solution (e.g. saline, dextrose
solution, etc.), preferably sterile, to reconstitute Product R to
form a solution for injection purposes.
[0064] In another embodiment, a kit of the invention further
comprises a needle or syringe, preferably packaged in sterile form,
for injecting Product R, and/or a packaged alcohol pad.
Instructions are optionally included for administration of Product
R by a clinician or by the patient.
[0065] Kits are also provided for carrying out the combination
therapies of the present invention. In one embodiment, a kit
comprises a first container containing Product R and a second
container containing a chemotherapeutic agent for treatment of
cancer.
[0066] The kit may for example comprise metal or plastic foil, such
as a blister pack. The kit may be accompanied by one or more
reusable or disposable device(s) for administration (e.g, syringes,
needles, dispensing pens) and/or instructions for
administration.
5. EXAMPLES
5.1 Example 1: Method for Preparing Product R
[0067] Suspend about 35.0 g of casein, about 17.1 g of beef
peptone, about 22.0 g of nucleic acid (RNA), about 3.25 g bovine
serum albumin in about 2.5 liters of water for injection USP at
about 3 to 7.degree. C. in a suitable container and gently stir
until all the ingredients have been properly wet. Carefully add
while stirring about 16.5 g of sodium hydroxide (reagent grade ACS)
and continue stirring until sodium hydroxide completely dissolved.
Autoclave at about 9 lbs pressure and 200-230.degree. F. for a
period of time until RNA is completely digested, for example, about
4 hours. At the end of the period, the autoclave is stopped and the
reaction flask and contents are permitted to slowly cool to ambient
temperature. Then cool for at least six hours at about 3-8.degree.
C. The resulting solution is filtered through 2 micron and 0.45
micron filters using inert gas such as nitrogen or argon at low
pressure (1-6 psi). In a similar manner the solution is filtered
again through 0.2 micron pyrogen retention filters. The resulting
filtrate is sampled and assayed for total nitrogen. A calculation
is then performed to determine the quantity of cooled water for
injection to be added to the filtrate to yield a diluted filtrate
with a nitrogen content between about 165-210 mg/10 ml, the final
volume is approximately 5 liters. The pH is then adjusted with
either concentrated HCl (reagent grade ACS) or 1.0 normal NaOH to
about 7.3-7.6 range. The diluted solution is then filtered again
through 0.2 micron filters with inert gas at low pressure. The
final filtrate is then filled and sealed into 2 ml glass ampules
while in an inert gas atmosphere. The ampules are collected and
autoclaved for final sterilization at 240.degree. F. and 20 to 30
pounds pressure for about 30 minutes. Following the sterilization
cycle, the ampules with Product R are cooled and washed.
[0068] All quantities are subject to plus or minus 2.5% variation
for pH, volume, and analytical adjustments.
5.2 Example 2
[0069] Case 1 is that of a 36 year old white male with a history of
widely metastatic and progressive malignant melanoma that involved
brain, lung, liver, and spleen. He began a regimen of temador
(temazolamide) 75 mg/m.sup.2, and thalidomide 400 mg qhs. He
tolerated the treatment with significant side effects--extreme
fatigue and weight loss with loss of appetite because of
gastric-intestinal (GI) toxicity caused by the chemotherapy. His
performance status was KPS 60/100 when Product R 2 cc SC qd was
added at his request. Within 24 hours of injection, he reported a
substantial improvement in mood, appetite, and willingness to
continue with his treatment. He maintained a normal CBC. This went
on for approximately 2 weeks. Unfortunately, he then had a bleeding
episode from a cerebral metastasis, and was noted to have
progressed. He underwent palliative radiation and subsequently died
of complications of pneumonia. He was not able to continue with
Product R during his final hospitalization.
5.3 Example 3
[0070] Case 2 is that of a 65 year old white male with a history of
widely metastatic bladder cancer involving omentum and mesentery.
He suffered from a severe neuropathy related to Taxol chemotherapy
and progressed on it after an initial dramatic response. Gemzar was
given with further progression and severe GI toxicity, manifested
as loss of appetite, and extreme fatigue. Finally as a last attempt
at palliation Taxotere with Product R therapy was given. The
patient was able to improve his energy level, appetite, and was
able to tolerate the Taxotere chemotherapy with no additional
neurotoxicity, at essentially average dose (60 mg/m.sup.2). He
remained an actively treated patient and maintained his weight and
heme parameters while on Product R, until he died 2 months later of
a stroke.
5.4 Example 4
[0071] Case 3 is that of a 34 year old black female with advanced
Hodgkin's disease who failed ABVD and stem cell transplant. She was
not able to tolerate palliative Navelbine chemotherapy because of
extreme fatigue and weight loss. She required doses of between
12-24 mg of dexamethasone to maintain any energy or appetite, and
was transfusion dependent. In addition, cervical lymphadenopathy
was causing severe pain and discomfort. Product R was added to the
Navelbine regimen. Within 2 weeks the patient was maintaining
weight, appetite, and although not complete, had an improvement in
her ability to maintain a red cell count and platelet count.
Because of extensive marrow involvement of the HD, she required
intermittent use of growth factors. With the exception of one
episode of blood borne sepsis due to an infected Mediport, the
patient had been doing well with a significant decrease in overall
lymphadenopathy and splenomegaly, based on a CT scan. She died 6
weeks later, when Product R was discontinued, of bacteremia.
5.5 Example 5
[0072] Case 4 is that of a 72 year old male recently diagnosed with
acute lymphocytic leukemia. His story is the most dramatic. He
arrived in New York on Jan. 10, 2001 after his oncologist in
Florida stated that bone marrow done on January 7 showed relapse
with 25% bias ts. At that point, the dose of Product R which was
started 3 weeks before was increased from 2 cc to 4 cc per day. He
was profoundly fatigued and had lost 15 pounds. The WBC was 800
with 2000 blasts. Hemoglobin was 11.0, and platter count was
110,000. Bactrim given as prophylactic therapy in Florida was
discontinued and he was weaned off prednisone. He continued with
Product R therapy for approximately 6 weeks of Product R treatment.
He last received vincristine at the end of December 2000. He
received 3 doses of G-CSF. By the next week his WBC improved and
the G-CSF discontinued. Two weeks later he had a WBC of 10,000 with
a normal differential. Hemoglobin was 14.2, hematocrit was 45, and
platelet count was 157,000. A rare atypical lymphocyte was seen. A
bone marrow aspirate and biopsy were done on Jan. 30, 2001 which
revealed an occasional blast cell, as did the biopsy. Normal
myeloid lines were seen with mild erythroid hyperplasia. The
patient felt great, gained weight, and had improved strength. He
entered into a remission without additional cytotoxic therapy, only
taking Product R.
[0073] All references cited herein are incorporated herein by
reference in their entirety and for all purposes to the same extent
as if each individual publication or patent or patent application
was specifically and individually indicated to be incorporated by
reference in its entirety for all purposes.
[0074] Many modifications and variations of this invention can be
made without departing from its spirit and scope, as will be
apparent to those skilled in the art. The specific embodiments
described herein are offered by way of example only, and the
invention is to be limited only by the terms of the appended claims
along with the full scope of equivalents to which such claims are
entitled.
Sequence CWU 1
1
2 1 31 PRT Artificial sequence Description of artificial sequence
synthetic peptide 1 Lys Val Leu Pro Val Pro Gln Lys Ala Val Pro Tyr
Pro Gln Arg Asp 1 5 10 15 Met Pro Ile Gln Ala Phe Leu Leu Tyr Gln
Glu Pro Val Leu Gly 20 25 30 2 21 PRT Artificial sequence
Description of artificial sequence synthetic peptide 2 Gly Glu Ile
Pro Asp Ala Gly Gly Arg Ile Val Asp Tyr Tyr Val Gly 1 5 10 15 Phe
Ser Asp Ser Val 20
* * * * *