| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1994: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1993: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1992: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
1) Cytotoxic effect of simvastatin, HMG-CoA reductase inhibitor, on human pancreatic adenocarcinoma cells containing mutant ras gene. The dose-dependent (0.1-100mug/ml) cytotoxicity of simvastatin (SV) to human (MIA PaCa-2, Panc-1, HPC-3, HPC-4, PK-1, PK-9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. The concentration of SV necessary to achieve 50% cytotoxicity was about 10mug/ml and at this concentration of SV,DNA synthesis assayd in terms of [^3H] thymidine uptake, isoprenylation of p21^<ras> examined by Western botting, and cell progression from G1 to S prase of the cell cycle analyzed by flow cytometry were all inhibited.
2) cytotoxic effect of gliotoxin, a farnesyl protein transferase (FPTase) on H-ras transformed fibroblast. Gliotoxin (GT) inhibited farnesylation of p21^<ras> dose-dependently (0.6-10mug/ml) within 24hr by Western blotting. The concentration necessary to achieve 50% cytotoxity was about 0.3mug/ml, determined by MTT assay for 72hr incubation. DNA fragmentation was observed by agalose get at a cytotoxic dose of GT,indicating that the mode of cell death is apoptosis.
In conclusion, these results suggest that above compound are possibly useful as anti-tumor agents for the carcinoma cells containing mutant ras gene.
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