Synergistic effects of geldanamycin and antitumor drugs.
OBJECTIVE
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.


CONCLUSIONS
These results suggest that GDM, as a biochemical modulator targeting Hsp90 function, may be potentially useful in cancer chemotherapy.
Liao
Z Y
ZY
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Zhang
S H
SH
Zhen
Y S
YS
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D016227:Benzoquinones; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D047029:Lactams, Macrocyclic; D008113:Liver Neoplasms / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D016685:Mitomycin / Q000008:administration & dosage; D009368:Neoplasm Transplantation; D011809:Quinones / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; D016685:Mitomycin; D002945:Cisplatin; C001277:geldanamycin