Combination therapy: lonidamine, hyperthermia, and chemotherapy against the RIF-1 tumor in vivo

Lonidamine enhances the cytotoxicity in vitro of several conventional antitumor drugs as well as that of hyperthermia (HT). We have investigated the possibility that such enhancement can also be demonstrated in vivo against the RIF-1 tumor system. Two assays were used to examine antitumor activity: tumor growth delay and clonogenicity of cells obtained from tumors from treated animals. We used drug (and HT) doses that by themselves did not achieve significant cell killing. The drugs whose interaction with lonidamine was tested were: cis-diamminedichloroplatinum (CDDP), mitomycin C (MMC), bleomycin, 5-fluorouracil, and nitrosourea. Of these only CDDP and MMC yielded positive data. Both assays gave essentially the same results, showing that antitumor activity reflected direct cell killing. CDDP and MCC activity was also enhanced by HT. When we combined all three modalities, however, the results of the trimodality therapies were no better than that of individual bimodality treatments. These last results suggest that lonidamine and HT have similar mechanisms, most likely inhibition of repair of DNA damage. Our data do suggest that lonidamine may have a role in multidrug therapies that include either CDDP or MMC as a component of the treatments.