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

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Abstract
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.