Mechanisms of combined effects of gamma-interferon and 5-fluorouracil on human colon cancers implanted into nude mice.

The purpose of these studies was to determine the possible mechanisms responsible for the therapeutic effects of systemic administration of 5-fluorouracil (FUra) and gamma-interferon on disseminated human colon cancer. We used several human carcinoma cell lines that were established from different surgical specimens. Some lines were selected in nude mice for increased metastatic potential, and one line was selected in vitro for resistance to human recombinant gamma-interferon (r-IFN-gamma). In initial in vitro studies, FUra was cytostatic against all the human cell lines but did not produce cytolysis in any of the lines tested. The two r-IFN-gamma were species specific for both antitumor and immunomodulatory effects. Human r-IFN-gamma produced cytostatic and cytolytic effects against sensitive human colon carcinoma cells but did not activate tumoricidal properties in mouse macrophages. In contrast, mouse r-IFN-gamma had no direct cytotoxic effects against any of the human colon carcinoma lines but did activate tumoricidal properties in mouse macrophages. Human colon carcinoma cells (sensitive or resistant to human r-IFN-gamma) were implanted into the spleens of nude mice. Three days later, we began treatments with FUra and human or mouse r-IFN-gamma. In all experiments, the combination of FUra with mouse r-IFN-gamma produced the best therapeutic effects against growth of the cells in the spleen and in the liver. Because the mouse r-IFN-gamma is devoid of direct antitumor effects (against human tumor cells) but is a potent macrophage activator, these results suggest that the antitumor effects were due to direct antitumor effects of FUra and to activation of host defense mechanisms by the r-IFN-gamma.