OHNISHI Shin UNIVERSITY OF TOKYO,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部(病), 助手 (00183236)
KODAMA Tatsuhiko UNIVERSITY OF TOKYO,FACULTY OF MEDICINE,ASSISTANT PROFESSOR, 医学部, 助手 (90170266)
|Budget Amount *help
¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1993 : ¥200,000 (Direct Cost : ¥200,000)
Fiscal Year 1992 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1991 : ¥800,000 (Direct Cost : ¥800,000)
In search of a new canther thrapy, we investigated whether cancer therapy is possible by way of inhibiting ras protein farnesylation. In the first series of experiments, we investigated what factors derived from mevalonate, except for cholesterol, are essential for cell growth. We supposed that farnesyl moiety derived from farnesyl-pyrophosphate is the putative factor, and we tried to prove this hypothesis. In cell culture experiments, compactin, an HMG-CoA reductase inhibitor, suppressed the growth of every cell line tested, and the degree of growth suppress was similar in ras-mutated cell lines and non-ras-mutated ones. We noticed that mevalonate fails to recover the cell growth suppressive effect of HMG-CoA reductase inhibitors. From these results, we cannot couclude that the cell growth inhibiting effect of compactin is mediated by expression blockade of ras proteins. A synthetic tetrapeptide (CVIM), which represents a common motif in the C-terminus of ras proteins and is known to competetively inhibit farnesyl : protein transferase, was synthethized and was used in cell culture system, but the peptide failed to pass through the cell membrane and we could not obtain results.
As an in vivo study, we tried to see whether a HMG-CoA reductase inhibitor can prevent cancer occurrence in a spontaneously-occurring mouse cancer system. Simvastatin was given to C3H mice. However, we failed to demonstrate significant cancer preventing effects of the agent. Finally, a small clinical therapy trial was conducted in which three advanced cancer patients were treated with pravastatin. We failed to demonstrate significant anti-cancer effects in those patients. Thus, we could not obtain evidence that inhibition of ras protein farnesylation can mediate anti-tumor effects in this system. Further investigations will be necessary using specific farnesyl : protein transferase inhibitors.