SYNERGISTIC ENHANCEMENT OF CISPLATIN CYTOTOXICITY BY SN-38, AN ACTIVEMETABOLITE OF CPT-11, FOR CISPLATIN-RESISTANT HELA-CELLS

A cisplatin (cis-diamminedichloroplatinum (II); CDDP)-resistant HeLa c ell line (HeLa/CDDP cells), which showed more than 8-fold resistance t o CDDP compared to the parent cells, was newly established for this st udy. HeLa/CDDP cells accumulated 50% less platinum than the parent cel ls. 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 bot h cell lines. HeLa/CDDP cells had cross-resistance to diammine(1,1-cyc lobutanedicarboxylato)platinum(II) (CBDCA), (cis-diammine(glycolato)pl atinum (254-S), but not to inomethylpyrrolidine(1,1-cyclobutanedicarbo xylato) 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 1-piperidino)-1-piperidino]carbonyloxyca mptothecin (CPT-11). Furthermore, isobologram analysis indicated syner gistic interaction of CDDP and SN-38 only for HeLa/CDDP cells. The pre sent study suggests that combination therapy with CDDP and CPT-11 may be potentially useful in the treatment of some patients with CDDP-resi stant cancer.