格尔德霉素与抗肿瘤药物的协同作用

目的　研究格尔德霉素(Geldanamycin ,GDM)对人肝癌BEL-7402细胞周期的影响及顺铂和丝裂霉素C等药物联用GDM后的体外体内抗肿瘤作用。方法　用MTT法检测药物对肝癌BEL-7402细胞的生长抑制作用;流式细胞术分析细胞周期;小鼠移植性肝癌22模型研究药物的体内抗肿瘤作用。结果　MTT法测得GDM对BEL7402细胞的生长抑制作用IC₅₀为0.28μmol·L^-1。GDM 0.1,1.0和10μmol·L^-1处理BEL-7402细胞,引起S期细胞比例下降和G2/M期的明显阻断。在较低浓度,GDM 0.1μmol·L^-1和0.2 μmol·L^-1均增强一系列化疗药物包括顺铂、丝裂霉素C、阿霉素和阿糖胞苷对BEL-7402细胞的细胞毒作用。小鼠移植肝癌22模型中,GDM 0.38mg·kg-1增强顺铂和丝裂霉素C的抗肿瘤作用。协同作用十分显著,CDI<0.7。结论　这些结果提示GDM作为以抑制热休克蛋白90 (Hsp90 )功能为靶点的生化调节剂可能应用于肿瘤联合化疗的前景。

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 0.28 mumol.L-1. At concentrations of 0.1, 1.0, and 10 mumol.L-1, GDM reduced the proportion of S phase and induced G2/M arrest in BEL-7402 cells. At relatively low cytotoxic concentration, 0.1 or 0.2 mumol.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.