Cell death in relation to cell cycle in a mouse ascites tumor growing in vivo after combined treatment with cisplatin and 5-fluorouracil.

The interaction of 5-fluorouracil (5-FU) and cisplatin (CDDP) was studied in Bp8 ascites sarcoma cells growing in mice. By density gradient centrifugation in Percoll solution, non-viable cells were separated from viable cells. Single drug treatment with doses of 12 and 36 mg/kg body weight of 5-FU and 0.4 and 0.8 mg/kg body weight of CDDP did not yield non-viable cells during the time period studied (96 h). Combination of the drugs increased the non-viable cells to about 10-25% depending on the doses given. This indicates a supra-additive cytotoxic effect. Analysis of the distribution of viable cells in the different cell cycle phases by flow cytometry showed an accumulation of cells in the S-phase after 5-FU and in the S- and G2-phases of the CDDP or combined 5-FU-CDDP treatment. Similar analysis of non-viable cells showed a similar cell cycle distribution, which suggests that supra-additive cytotoxicity is not cell cycle specific. By labeling the DNA of the tumor cells with [125T]-deoxyuridine and using whole body measurement, the cell loss was studied. No changes in cells loss after single drug and combined treatment were found during the observation time. The molecular basis for the interaction between 5-FU and CDDP should be elucidated.