Schedule-dependent interaction between vinblastine and cisplatin in Ehrlich ascites tumors in mice

Information on the in vivo antitumor efficiency of the combination of Vinca alkaloids in animal tumor models, especially vinblastine (VLB) with cisplatin [cis-diamminedichloroplatinum(II); CDDP] is very limited. Therefore, the aim of our study was to explore whether antitumor schedule dependence exists for the combination of CDDP and VLB on i.p. Ehrlich ascites tumors in mice. Animals were treated 3 days after tumor transplantation with VLB (0.006 mg/kg) or CDDP (0.05 mg/kg) alone, VLB followed by CDDP, and CDDP followed by VLB. The time interval between i.p. injections of the drugs was 24 h. Cell number was measured by counting viable cells using the trypan blue exclusion assay, cell platinum content by electrothermal atomic absorption spectrometry, DNA distribution pattern using flow cytometry, apoptosis by flow-cytometric terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell morphology. Combination of CDDP and VLB resulted in additive interaction when VLB preceded CDDP as determined from cell survival data 24 h after completion of the therapy and in increased platinum content (two times) compared with the same combination in a reverse schedule (CDDP given before VLB), which resulted in antagonism. None of the treatment combinations induced apoptosis. We propose that the observed increase in antitumor effectiveness is mainly due to higher platinum accumulation in tumor cells, which we unambiguously demonstrated by measurement of platinum content in the tumor cells, leading to increased cytotoxicity as well as to cell cycle-dependent effects of VLB and CDDP.