Synergistic enhancement of cisplatin cytotoxicity by SN-38, an active metabolite of CPT-11, for cisplatin-resistant HeLa cells.

A cisplatin (cis-diamminedichloroplatinum(II); CDDP)-resistant HeLa cell line (HeLa/CDDP cells), which showed more than 8-fold resistance to CDDP compared to the parent cells, was newly established for this study. HeLa/CDDP cells accumulated 50% less platinum than the parent cells. There was no difference in intracellular glutathione (GSH) content between the parent and HeLa/CDDP cells. The dose modification factor by DL-buthionine-S,R-sulfoximine (BSO) pretreatment was similar in both cell lines. HeLa/CDDP cells had cross-resistance to diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA), (cis-diammine(glycolato)platinum (254-S), but not to (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) (DWA2114R), adriamycin, or VP-16. HeLa/CDDP cells showed a collateral sensitivity to 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11). Furthermore, isobologram analysis indicated synergistic interaction of CDDP and SN-38 only for HeLa/CDDP cells. The present study suggests that combination therapy with CDDP and CPT-11 may be potentially useful in the treatment of some patients with CDDP-resistant cancer.