Inhibition of cis-diamminedichloroplatinum (II)-induced DNA interstrand cross-link removal by 7-ethyl-10-hydroxy-camptothecin in HST-1 human squamous-carcinoma cells.
The combination of cis-diamminedichloroplatinum(II) (CDDP) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), a topoisomerase-I inhibitor, has been shown to be synergistic in vitro and clinically active against several human cancers refractory to chemotherapy. To elucidate the mechanism of the synergistic cytotoxicity of CDDP and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of CPT-11, we studied the interaction of these agents using an HST-1 human squamous-carcinoma cell line. Cells were exposed to the IC50 concentration of SN-38 (5.0 ng/ml) for 1 hr and various concentrations of CDDP for 1 hr in several different treatment schedules. SN-38 augmented the anti-tumor activity of CDDP in all schedules, with maximal synergy observed with simultaneous administration. Evaluation of the kinetics of the removal of DNA interstrand cross-links, measured by alkaline elution, showed significant reduction of this removal in the cells exposed to SN-38 and CDDP, as compared with the cells exposed to CDDP alone. No differences, however, were found in the initially attained level of DNA interstrand cross-links induced by CDDP between these cells. Moreover, the intracellular accumulation of platinum measured by atomic-absorption spectrophotometry, was virtually identical between these cells. These results indicate that SN-38 can modulate the removal of platinum-DNA adducts, thereby potentiating the cytotoxicity of CDDP, suggesting a critical role for topoisomerase I in the repair of DNA interstrand cross-links.
Masumoto
N
N
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Japan.
Nakano
S
S
Esaki
T
T
Fujishima
H
H
Tatsumoto
T
T
Niho
Y
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004264:DNA Topoisomerases, Type I / Q000502:physiology; D006801:Humans; D000077146:Irinotecan; D014062:Tongue Neoplasms / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002945:Cisplatin; D002166:Camptothecin