Metronidazole enhances the cytotoxic synergism produced by the combination of 1-β-arabinofuranosylcytosine and cis-diamminedichloroplatinum

Metronidazole (MZ) was evaluated as a single agent or in combination with CDDP and araC for its cytotoxic effects on five established human colon carcinoma cell lines. MZ alone produced little cytotoxicity at 1 h drug incubation. The cytotoxicity was detectable only after 2 h incubation and increased as a function of duration of treatment, suggesting a time-dependent rather than a dose-dependent cytotoxic effect. MZ had no effect on CDDP- or araC-induced cytotoxicity, whereas MZ enhanced the synergism resulting from the combination of two antitumor agents on the human colon tumor cell lines tested. Such enhancement was more pronounced on cells growing in stationary rather than in exponential phase. MZ not only produced a reversible S-phase arrest but also lessened the CDDP-produced inhibition on the incorporation of araC into DNA. However, it did not enhance CDDP-induced DNA cross-linkings, with or without araC. Our results indicated that MZ enhanced the synergism produced by two antitumor drugs in combination and that enhancement was accompanied by an increase in S-phase population and of the incorporation of araC into nucleic acids.