Cytotoxicity of simvastatin to pancreatic adenocarcinoma cells containing mutant ras gene.

Simvastatin (SV), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, inhibits the synthesis of mevalonic acid. The dose-dependent (0.1-100 micrograms/ml) cytotoxicity of SV towards human (MIAPaCa-2, Panc-1, HPC-1, HPC-3, HPC-4, PK-1, PK-9) and hamster (T2) pancreatic carcinoma cell lines was determined by MTT assay. At up to 20 micrograms/ml of SV, the effect was reversible and was restored by 60 micrograms/ml mevalonic acid. Point mutation of Ki-ras at codon 12 in each cell line was detected by means of the modified polymerase chain reaction. The concentration of SV necessary to achieve 50% cytotoxicity was about 10 micrograms/ml, and at this concentration of SV, DNA synthesis assayed in terms of [3H]thymidine uptake, isoprenylation of p21ras examined by Western blotting and cell progression from G1 to S phase of the cell cycle analyzed by flow cytometry were all inhibited. Isoprenylation inhibitors of p21ras, such as SV, are expected to be useful for the treatment of pancreatic cancer.