Inhibition of cis‐diamminedichloroplatinum (II)‐induced DNA interstrand cross‐link removal by 7‐ethyl‐10‐hydroxy‐camptothecin in HST‐1 human squamous‐carcinoma cells

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Abstract
The combination of cis‐diamminedichloroplatinum(II) (CDDP) and 7‐ethyl‐10‐[4‐(I ‐piperidino)‐I ‐piperidino]carbonyloxycamptothecin (CPT‐I I), a topoisomerase‐l 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‐I human squamous‐carcinoma cell line. Cells were exposed to the IC50 concentration of SN‐38 (5.0 ng/ml) for I 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. © 1995 Wiley‐Liss Inc.