In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction

Among the numerous clinical regimens used in combination chemotherapy, syne rgy is particularly marked in combinations containing cisplatin (CDDP), How ever, the clinical use of CDDP is sometimes limited due to its nephrotoxici ty, Nedaplatin (NDP) is a second-generation platinum complex with reduced n ephrotoxicity that may substitute for CDDP or even surpass it for use in co mbination with other drugs. We investigated the effects of combinations of NDP and other anticancer drugs on the growth of human small cell lung cance r cells (SBC-3) and non-small cell lung cancer cells (PC-14) using a three- dimensional analysis model, Among the combinations tested, the combination of NDP and irinotecan (CPT-11) showed the most marked synergistic interacti on, and the synergism has also been observed against PC-14 cells. With rega rd to treatment schedule, a remarkable synergistic interaction was produced by concurrent exposure to NDP and CPT-11, On the other hand, sequential ex posure to the two drugs led only to additivity. To analyze the interaction between the drugs, the effect of NDP on the 7-ethyl-1-hydroxy-CPT (the acti ve form of CPT-11)-induced inhibitory effect on DNA topoisomerase I was exa mined. The topoisomerase I-inhibitory effect of 7-ethyl-1-hydroxy-CPT was e nhanced 10-fold in the presence of NDP at microgram/milliliter concentratio ns. These biochemical interactions might be responsible for the synergistic interaction between NDP and CPT-11, These results suggest that the combina tion of NDP with CPT-11 may be clinically useful for the chemotherapy of lu ng cancer.