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Antitumor Effects of -Interferon and -Interferon on a Murine Renal Cancer (Renca) in Vitro and in Vivo¹

Biological Carcinogenesis Development Program, Program Resources Incorporated [T. J. S., T. A. W., K. M.], and Laboratory of Experimental Immunology, Biological Response Modifiers Program, Division of Cancer Treatment, NCI-Frederick Cancer Research Facility, Frederick, Maryland 21701-1013

Previous studies have shown that established murine renal cancer (Renca) can be successfully treated with the investigational drug flavone acetic acid (FAA) used in combination with recombinant interleukin 2 (IL-2). Additional experiments demonstrated that the in vivo administration of FAA rapidly induced the expression of the genes, as well as the biologically active proteins, for - and ß-interferons (IFNs) as well as tumor necrosis factor . Both IFN- and IFN- have been shown to have direct antiproliferative effects against some tumors, as well as being potent immunodulators for the induction of antitumor effector cells. Thus, the present study was designed to investigate the ability of IFN- and/or IFN- to mediate direct antiproliferative effects against Renca in vitro as well as to cause regression of Renca in vivo. The present study confirms that RAA and/or IL-2 are inactive against Renca in vitro, further suggesting an indirect mechanism for FAA-induced antitumor effects in vivo. However, the exposure of Renca in vitro to recombinant human IFN-A/D, murine IFN- or murine IFN-ß resulted in a dose dependent growth inhibition of Renca as assessed by the microculture tetrazolium dye incorporation assay. Very little growth inhibition was induced by recombinant murine IFN-. Interestingly, IFN- (100–1000 units/ml) when combined with very low doses of recombinant murine IFN- (1–10 units/ml) yielded significantly more pronounced growth inhibition than either cytokine alone. This effect was most evident by 5 days of culture where combinations of 100–1000 units/ml recombinant human IFN-A/D with 1–5 units/ml recombinant murine IFN- yielded growth inhibition in the range of 45–99%. In order to determine whether the mechanisms for the antitumor activity of recombinant human IFN-A/D and recombinant murine IFN- was due to their direct antiproliferative effects, we also studied the efficacy of these combinations against i.p. Renca in athymic mice. In contrast to the potent antitumor effects observed in euthymic mice, the combination of IFN- and IFN- only slightly increased mean survival times in athymic mice and no long term survivors were obtained. Subsequent studies demonstrated that most mice (77%) cured of peritoneal Renca by recombinant human IFN-A/D plus recombinant murine IFN- were immune to rechallenge. Therefore the combination of IFN- and IFN- may directly inhibit the growth of Renca, but a major effect of IFNs in vivo must be to contribute to the induction of an anti-Renca immune response.

¹ This project has been funded at least in part with Federal funds from the Department of Health and Human Services under Contract NO1-CO-74102. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government.

By acceptance of this article, the publisher or recipient acknowledges the right of the United States Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.

² To whom requests for reprints should be addressed.

Received 3/19/90. Revised 5/22/90.

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