Different interaction of cisplatin and etoposide on in vivo and in vitro tumor systems

The effect of cisplatin (CDDP) in combination with etoposide (VP16) was examined on four human cell lines (one colon adenocarcinoma, LoVo; one ovarian carcinoma, IGROV-1; two small cell lung cancers, NCI-H146 and NCI-N592; and two murine leukemias, P388 and L1210). Simultaneous exposure to CDDP and subtoxic concentrations of VP16 for 1 h produced a cell killing in all cell lines comparable to that achieved by CDDP alone. Sequential exposure of NCI-H146 and NCI-N592 to CDDP for 1 h followed by VP16 for 96 h again produced an additive effect. When two of these cell lines were treated in in vivo models (i.p. P388 leukemia, s.c. NCI-N592) with suboptimal doses of the two drugs, a potentiation of the antitumor effects of the two drugs in simultaneous combination was evidenced by the increase in survival time and in the number of 'cures' in P388 leukemia bearing mice and by the inhibition of tumor size in NCI-N592. This comparative study, using the same cell lines in vitro and in vivo, indicates that the CDDP-VP16 potentiation observed in vivo does not reflect a specific interaction at the cellular-biochemical level. The results support the therapeutic interest of this combination (presumably as a result from favorable pharmacological interactions) even despite the lack of potentiation at cellular level, under comparable conditions of treatment.