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Effect of Hyperthermia on the Antiproliferative Activities of Murine -, ß-, and -Interferon: Differential Enhancement of Murine -Interferon¹

Department of Microbiology, The University of Texas Medical Branch, Galveston, Texas 77550 [W. R. F., C. M. F.], and Laboratory of Experimental Pathology, National Cancer Institute, Frederick Cancer Research Facility, Frederick, Maryland 21701 [T. D. G.]

Fever is frequently an important side effect of interferon (IFN) therapy. Studies have shown that culturing interferon-treated cells at elevated temperature heightens the antiproliferative activity of IFN- and IFN-ß. Since IFN- has also been shown to be a potent antiproliferative agent, the effect of elevated temperature on IFN- activity was compared to its effect on IFN- and IFN-ß. Mouse B-16 melanoma cells were simultaneously cultured under cloning conditions at a range of temperatures (37.3, 38.1, 38.6, and 39.4°C) in the presence of MuIFN-, MuIFN-ß, and MuIFN-. The antiproliferative activities of all three interferons were enhanced by incubation at the elevated temperatures. However, the elevated temperatures had a more dramatic enhancing effect on the antiproliferative activity of MuIFN- (10-fold enhancement) than of either MuIFN- or MuIFN-ß (2.9- and 3.4-fold enhancement, respectively). Next, the enhancing effect of elevated temperature (39.4°C) was examined for a range of interferon concentrations. The degree of the enhancing effect increased with increasing concentrations of MuIFN- but not with increasing concentrations of MuIFN- or MuIFN-ß. Enhancing effects of temperature as high as 14-fold were observed for 100 units of MuIFN-/ml. This dramatic enhancement was observed for both natural and recombinant MuIFN- and was neither a function of greater relative perception of MuIFN- titer at elevated temperature nor a function of greater relative stability of MuIFN- at the elevated temperature. The differential enhancement of MuIFN- activity by elevated temperature appeared to be specific for the antiproliferative activity, since the antiviral activity of MuIFN- was not relatively more enhanced at 39.4°C than were the antiviral activities of MuIFN- and MuIFN-ß. These results suggest that fever may be an important factor in maximizing the antitumor effects of MuIFN- and perhaps of human IFN-. They also raise the possibility that a combination treatment regimen of hyperthermia and interferon therapy, particularly IFN- therapy, may provide a significant antitumor effect.

¹ Supported by USPHS Grant CA26475 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Department of Microbiology, The University of Texas Medical Branch, Galveston, TX 77550.

Received 4/18/85. Revised 9/ 3/85. Accepted 9/16/85.