SYNERGISTIC EFFECTS OF GELDANAMYCIN AND ANTITUMOR DRUGS

AIM To study the effect of geldanamycin (GDM) on cell cycle of human hepatoma BEL-7402 cells and the antitumor activity of cisplatin and mitomycin C in combination with GDM in vitro and in vivo. METHODS MTT assay was used to determine the growth inhibition of hepatoma BEL-7402 cells. Cell cycle was analyzed by flow cytometry. Transplantable murine hepatoma 22 model was used to evaluate the antitumor activity of drugs in vivo. RESULTS The IC₅₀ value of GDM for hepatoma BEL-7402 cells by MTT assay was found to be 0.28μmol·L^-1. At concentrations of 0.1, 1.0, and 10 μmol·L^-1 , GDM reduced the proportion of S phase and induced G 2/M arrest in BEL-7402 cells. At relatively low cytotoxic concentration, 0.1 or 0.2 μmol·L^-1, GDM markedly potentiated the cytotoxicity of a series of chemotherapeutic agents including cisplatin, mitomycin C, adriamycin and cytarabine against BEL 7402 cells. The inhibition of tumor growth by cisplatin and mitomycin C was also enhanced in transplantable hepatoma 22 bearing mice when these agents were administered in combination with GDM 0.38 mg·kg^-1. The synergistic effects were very significant with CDI<0.7. CONCLUSION These results suggest that GDM, as a biochemical modulator targeting Hsp90 function, may be potentially useful in cancer chemotherapy.