The purpose of these studies was to determine the possible mechanisms responsible for the therapeutic effects of systemic administration of 5-fluorouracil (FUra) and γ-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 γ-interferon (r-IFN-γ). 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-γ were species specific for both antitumor and immunomodulatory effects. Human r-IFN-γ 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-γ 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-γ) were implanted into the spleens of nude mice. Three days later, we began treatments with FUra and human or mouse r-IFN-γ. In all experiments, the combination of FUra with mouse r-IFN-γ produced the best therapeutic effects against growth of the cells in the spleen and in the liver. Because the mouse r-IFN-γ 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-γ.

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This work was supported in part by Grant R35-CA 42107 from the National Cancer Institute, NIH, and by the AMOCO Foundation.

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