Contradictory antitumor efficacies produced by the combination of DNA attacking drugs and polyamine antimetabolites

The antitumor effects of two polyamine antimetabolites, alpha-difluoromethylornithine (DFMO) and methylglyoxal-bis-guanylhydrazone (MGBG), when combined with cis-diamminedichlroplatinum (CDDP) or mitomycin C (MMC), were studied using human gastric cancer cells xenotransplanted into nude mice. DFMO 1000 mg/kg and MGBG 50 mg/kg were given intraperitoneally for 6 successive days, while CDDP 3 mg/kg or MMC 2 mg/kg was given every second day. Although DFMO and MGBG plus MMC did suppress the tumor growth, the combination with CDDP led to no suppression, and rapid growth occurred after the cessation of therapy. The inhibition of tumoral DNA biosynthesis and a decline in polyamine levels, were also not observed. The polyamine antimetabolites when used with CDDP did not produce the desired antitumor efficacy, even though the platinum concentration in the tumor tissue was high. On the contrary, however, DFMO and MGBG when combined with MMC did suppress tumor growth, inhibited DNA biosynthesis, and tissue polyamine levels were low. These results suggest that though CDDP and MMC belong to a similar category of DNA attacking, bifunctional alkylating agents, the findings of these two drugs are contradictory. Here, the mechanism of action no doubt plays a contributory role.