Synergistic Enhancement of Cisplatin Cytotoxicity by SN-38, an Active Metabolite of CPT-11, for Cisplatin-resistant HeLa Cells

A cisplatin ( cis -diamininedichloroplatinuin(II); CDDP)-resistant HeLa cell line (HeLa/CDDP cells), which showed more than 8-fold resistance to CDDF 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 (l, l-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-hydroxycampto-thecin (SN-38), an active metabolite of 7-ethyl-10-[4-(l-piperidino)-l-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 he potentially useful in the treatment of some patients with CDDP-resistant cancer.