AI Article Synopsis

  • The combination of CDDP and CPT-11 shows enhanced cancer-fighting properties, effective against chemotherapy-resistant human cancers.
  • SN-38, an active metabolite of CPT-11, increases the effectiveness of CDDP when administered simultaneously, demonstrating synergistic cytotoxicity in HST-1 human squamous-carcinoma cells.
  • The study suggests that SN-38 influences the removal of DNA damage caused by CDDP, highlighting the importance of topoisomerase I in the DNA repair process related to platinum-based treatments.

Article Abstract

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.

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http://dx.doi.org/10.1002/ijc.2910620114DOI Listing

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