IN-VIVO ENHANCED ANTITUMOR-ACTIVITY OF CARMUSTINE [N,N'-BIS(2-CHLOROETHYL)-N-NITROSOUREA] BY SIMVASTATIN

The effects of a combination of simvastatin, a cholesterol-lowering ag ent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on e xperimental C-6 glioma were studied in vitro and in vivo. In vitro sim vastatin and BCNU alone inhibited cell proliferation in a dose-depende nt fashion. A subliminal concentration of simvastatin (0.1 mu M) marke dly and synergistically increased the BCNU toxicity to C-6 glioma cell s. The cytofluorimetric analysis of DNA from simvastatin-treated C-6 g lioma cells showed, besides the already described arrest in G(1), an a rrest/retardation in G(2)-M. Mitotic index from C-6 cells incubated wi th simvastatin (10 mu M) decreased by about 90%, indicating a specific C-6 arrest/retardation in G(2). The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultu red cells. The combination of simvastatin and BCNU resulted predominan tly from the profound retardation of cells in the G(2)-M compartment o f the cell cycle. In vivo simvastatin (administered daily mixed with f ood) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C-6 glioma homografts ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of th e lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) r esulted in a significant growth delay (compared to either drug alone) in C-6 glioma (P < 0.05). There was no significant increase in toxicit y as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in viva support for the c ombined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment.