Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-14
2001-12-25
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000
Reexamination Certificate
active
06333333
ABSTRACT:
FIELD OF THE INVENTION
This invention describes novel methods of treating subjects afflicted with proliferative diseases such as cancers, tumors, or metastatic disease. In particular, this invention provides methods of inhibiting the proliferation of cells, more specifically cancer cells, comprising the combined use of (1) a farnesyl protein transferase (“FPT”) inhibitor and (2) an antineoplastic agent and/or radiation therapy.
BACKGROUND OF THE INVENTION
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Mutation and/or overexpression of certain oncogenes is frequently associated with cellular tranformation and human cancer. To acquire transforming potential, the precursor of the ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors. Mutated, oncogenic forms of ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1934 to 1937, (1993)). Proteins other than ras may play a part in tumorigenicity and may also require farnesylation for biological activity.
International Patent Publication Number WO92/11034 (published Jul. 9, 1992) discloses a method of increasing the sensitivity of a tumor to an antineoplastic agent (in cases where the tumor is resistant to the antineoplastic agent), by the concurrent administration of the antineoplastic agent and (inter alia) a potentiating agent of the formula:
wherein the dotted line represents an optional double bond, X′ is hydrogen or halo, and Y′ is hydrogen, substituted carboxylate or substituted sulfonyl. For example, Y′ can be, amongst others, —COOR′ wherein R′ is C-1 to C-6 alkyl or substituted alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl, 2-, 3- or 4-piperidyl or N-substituted piperidyl. Y′ can also be, amongst others, SO
2
R′ wherein R′ is C-1 to C-6 alkyl, phenyl, substituted phenyl, C-7 to C-12 aralkyl or substituted aralkyl. Examples of such potentiating agents include 11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridines such as Loratadine. Antineoplastic agents exemplified are: vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, and amsacrine. The WO92/11034 publication focuses on potentiating the antineoplastic agents through a specific mechanism of action: inhibition of multiple drug resistance.
In view of the need for improved treatments for proliferative diseases, particularly cancers, novel methods of treatment would be a welcome contribution to the art. The present invention provides just such methods of treatment.
SUMMARY OF THE INVENTION
The present invention provides methods of treating proliferative disease in a patient (e.g., a mammal such as a human) in need of such treatment, said treatment comprising administering, concurrently or sequentially, an effective amount of (1) a farnesyl protein transferase (FPT) inhibitor, and (2) an antineoplastic agent and/or radiation therapy. The methods of the present invention are particularly useful for the treatment of various cancers, especially epithelial cancers, e.g., prostate cancer, lung cancer, breast cancer, colorectal cancer, and pancreatic cancer. In preferred embodiments, the FPT inhibitor is combined with one of the following antineoplastic agents: gemcitabine, paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®), temozolomide, or Vincristine.
For instance, in a preferred embodiment, the present invention provides a method of treating cancer, comprising administering, concurrently or sequentially, an effective amount of (1) a farnesyl protein transferase (FPT) inhibitor, and (2) gemcitabine. In a particularly preferred embodiment, the cancer to be treated is a pancreatic cancer.
In another preferred embodiment, the present invention provides a method of treating cancer, comprising administering, concurrently or sequentially, an effective amount of (1) a farnesyl protein transferase (FPT) inhibitor, and (2) a microtubule affecting agent (e.g., paclitaxel).
In view of International Patent Publication WO92/11034, the present specification includes provision of a method of treating proliferative disease, said treatment comprising administering, concurrently or sequentially, an effective amount of (1) an FPT inhibitor, and (2) an antineoplastic agent and/or radiation therapy; with the proviso that when the FPT inhibitor is a compound of the formula:
wherein:
the dotted line represents an optional double bond;
X′ is hydrogen or halo; and
Y′ is hydrogen, —COOR′ wherein R′ is C
1
to C
12
alkyl or substituted alkyl, phenyl, substituted phenyl, C
7
to C
12
arylalkyl or substituted arylalkyl, 2-, 3- or 4-piperidyl or N-substituted piperidyl, wherein the substituents on said substituted C
1
to C12 alkyl are selected from amino and substituted amino, and the substituents on the substituted amino are selected from C
1
to C
6
alkyl, the substituents on said substituted phenyl and on said substituted aryl moiety of the C
7
to C
12
arylalkyl are selected from C
1
to C
6
alkyl and halo, and the substituent on said N-substituted piperidyl is C
1
to C
4
alkyl, or —SO
2
R′ wherein R′ is C
1
to C
12
alkyl, phenyl, substituted phenyl, C
7
to C
12
arylalkyl or substituted arylalkyl, wherein the substituents on said substituted phenyl and on said substituted aryl moiety of the C
7
to C
12
arylalkyl are selected from C
1
to C
6
alkyl and halo;
then the antineoplastic agent is not selected from vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B. emetine, maytansine, or amsacrine.
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Bishop Walter R.
Catino Joseph J.
Cutler David L.
Doll Ronald J.
Ganguly Ashit
Albanese Margaret M.
Gould James M.
Kutzenco Allan N.
Reamer James H.
Schering Corporation
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