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

Int J Cancer. 1995 Jul 4;62(1):70-5. doi: 10.1002/ijc.2910620114.


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.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cisplatin / metabolism
  • Cisplatin / pharmacology*
  • DNA Damage
  • DNA Repair / drug effects*
  • DNA Topoisomerases, Type I / physiology
  • Humans
  • Irinotecan
  • Tongue Neoplasms / metabolism
  • Tongue Neoplasms / pathology
  • Tumor Cells, Cultured


  • Antineoplastic Agents, Phytogenic
  • Irinotecan
  • DNA Topoisomerases, Type I
  • Cisplatin
  • Camptothecin