Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-06
2002-12-10
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...
C514S311000, C514S094000, C514S018700, C514S019300, C514S400000
Reexamination Certificate
active
06492410
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to combinations of compounds that can be used in the medicinal field to treat, prophylactically or otherwise, uncontrolled or abnormal proliferation of human tissues. Specifically, the present invention relates to the combination of (I) compounds that inhibit protein farnesyltransferase (PFT), which has been determined to activate ras proteins that in turn activate cellular division and are implicated in cancer and restenosis; and (2) compounds that inhibit HMG CoA reductase, a necessary component in the biosynthesis of farnesylpyrophosphate (FPP), which is essential in the activation of ras proteins by PFT.
BACKGROUND OF THE INVENTION
Ras protein (or p21) has been examined extensively because mutant forms are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas (Gibbs J. B.,
Cells
1991;65: 1, Cartwright T., et al.,
Chimica Oggi.,
1992; 10:26). These mutant ras proteins are deficient in the capability for feedback regulation that is present in native ras, and this deficiency is associated with their oncogenic action since the ability to stimulate normal cell division cannot be controlled by the normal endogenous regulatory cofactors. The recent discovery that the transforming activity of mutant ras is critically dependent on post-translational modifications (Gibbs J., et al.,
Microbiol. Rev.,
1989;53:171) has unveiled an important aspect of ras function and identified novel prospects for cancer therapy.
In addition to cancer, there are other conditions of uncontrolled cellular proliferation that may be related to excessive expression and/or function of native ras proteins. Post-surgical vascular restenosis is such a condition. The use of various surgical revascularization techniques such as saphenous vein bypass grafting, endarterectomy, and transluminal coronary angioplasty are often accompanied by complications due to uncontrolled growth of neointimal tissue, known as restenosis. The biochemical causes of restenosis are poorly understood and numerous growth factors and protooncogenes have been implicated (Naftilan A. J., et al.,
Hypertension,
1989; 13:706 and
J. Clin. Invest.,
83:1419; Gibbons G. H., et al.,
Hypertension,
1989;14:358; Satoh T., et al.,
Molec. Cell. Biol.,
1993;13:3706). The fact that ras proteins are known to be involved in cell division processes makes them a candidate for intervention in many situations where cells are dividing uncontrollably. In direct analogy to the inhibition of mutant ras related cancer, blockade of ras dependant processes has the potential to reduce or eliminate the inappropriate tissue proliferation associated with restenosis, particularly in those instances where normal ras expression and/or function is exaggerated by growth stimulatory factors.
Ras functioning is dependent upon the modification of the proteins in order to associate with the inner face of plasma membranes. Unlike other membrane-associated proteins, ras proteins lack conventional transmembrane or hydrophobic sequences and are initially synthesized in a cytosol soluble form. Ras protein membrane association is triggered by a series of post-translational processing steps that are signaled by a carboxyl terminal amino acid consensus sequence that is recognized by protein farnesyltransferase (PFT). This consensus sequence consists of a cysteine residue located four amino acids from the carboxyl terminus, followed by two lipophilic amino acids, and the C-terminal residue. The sulfhydryl group of the cysteine residue is alkylated by farnesylpyrophasphate (FPP) in a reaction that is catalyzed by PFT. Following prenylation, the C-terminal three amino acids are cleaved by an endoprotease and the newly exposed alpha-carboxyl group of the prenylated cysteine is methylated by a methyl transferase. The enzymatic processing of ras proteins that begins with farnesylation enables the protein to associate with the cell membrane. Mutational analysis of oncogenic ras proteins indicate that these post-translational modifications are essential for transforming activity. Replacement of the consensus sequence cysteine residue with other amino acids gives a ras protein that is no longer farnesylated, fails to migrate to the cell membrane and lacks the ability to stimulate cell proliferation (Hancock J. F., et al.,
Cell,
1989;57:1617, Schafer W. R., et al.,
Science,
1989;245:379, Casey P. J.,
Proc. Natl. Acad. Sci. USA,
1989;86:8323).
Recently, PFTs have been identified and a specific PFT from rat brain was purified to homogeneity (Reiss Y., et al.,
Bioch. Soc. Trans.,
1992;20:487-88). The enzyme was characterized as a heterodimer composed of one alpha-subunit (49 kDa) and one beta-subunit (46 kDa), both of which are required for catalytic activity. High level expression of mammalian PFT in a baculovirus system and purification of the recombinant enzyme in active form has also been accomplished (Chen W.-J., et al.,
J. Biol. Chem.,
1993;268:9675).
In light of the foregoing, the discovery that the function of oncogenic ras proteins is critically dependent on their post-translational processing provides a means of cancer chemotherapy through inhibition of the processing enzymes. The identification and isolation of a PFT that catalyzes the addition of a farnesyl group to ras proteins provides a promising target for such intervention. Ras farnesyltransferase inhibitors have been shown to have anticancer activity in several recent articles.
Ras inhibitor agents act by inhibiting farnesyltransferase, the enzyme that anchors the protein product of the ras gene to the cell membrane. The role of the ras mutation in transducing growth signals within cancer cells relies on the protein being in the cell membrane so with farnesyltransferase inhibited, the ras protein will stay in the cytosol and be unable to transmit growth signals: these facts are well-known in the literature.
A peptidomimetic inhibitor of farnesyltransferase B956 and its methyl ester B 1086 at 100 mg/kg have been shown to inhibit tumor growth by EJ-1 human bladder carcinoma, HT1080 human fibrosarcoma and human colon carcinoma xenografts in nude mice (Nagasu, T., et al.,
Cancer Res.,
1995;55:5310-5314). Furthermore, inhibition of tumor growth by B956 has been shown to correlate with inhibition of ras post-translational processing in the tumor. Other ras farnesyltransferase inhibitors have been shown to specifically prevent ras processing and membrane localization and are effective in reversing the transformed phenotype of mutant ras containing cells (Sepp-Lorenzino L., et al.,
Cancer Res.,
1995;55:5302-5309).
In another report (Sun J., et al.,
Cancer Res.,
1995;55:4243-4247), a ras farnesyltransferase inhibitor FT1276 has been shown to selectively block tumor growth in nude mice of a human lung carcinoma with K-ras mutation and p53 deletion. In yet another report, daily administration of a ras farnesyltransferase inhibitor L-744,832 caused tumor regression of mammary and salivary carcinomas in ras transgenic mice (Kohl, et al.,
Nature Med.,
1995;1(8):792-748). Thus, ras farnesyltransferase inhibitors have benefit in certain forms of cancer, including those dependent on oncogenic ras for their growth. However, it is well-known that human cancer is often manifested when several mutations in important genes occurs, one or more of which may be responsible for controlling growth and metastases. A single mutation may not be enough to sustain growth and only after two of three mutations occur, tumors can develop and grow. It is therefore difficult to determine which of these mutations may be primarily driving the growth in a particular type of cancer. Thus, ras farnesyltransferase inhibitors can have therapeutic utility in tumors not solely dependent on oncogenic forms of ras for their growth. For example, it has been shown that various ras farnesyltransferase inhibitors have antiproliferative effects in vivo against tumor lines with either wild-type or mutant ras (Sepp-Lorenzino, supra, 1995). In addition, there a
Leopold Judith
Newton Roger Schofield
Atkins Michael J.
Berven Heidi M.
Reamer James H.
Tinney Francis J.
Warner-Lambert & Company
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