Augmented antiproliferative effects of interferons at elevated temperatures against human bladder carcinoma cell lines.

The in vitro antiproliferative effects of interferons (IFN) against the human bladder carcinoma cell lines T24, RT4, HT1197, and 647V were evaluated at temperatures ranging from 37-41 degrees. At 37 degrees, the antiproliferative activities of IFN, either naturally produced or produced by recombinant DNA technology, were different against different cell lines. An increase in temperature markedly enhanced the antimitotic effect of IFN for all cells. For example, T24 cells grown at 37 degrees and treated with 200 units naturally produced IFN-alpha or IFN-beta per ml for 7 days were inhibited 50 to 60%. No change in cell proliferation occurred in untreated T24 cells grown at 39.5 degrees. Treatment with 200 units IFN-alpha or IFN-beta per ml at 39.5 degrees inhibited these cells 80 to 90%. Similar results were obtained with IFN produced by recombinant DNA technology and purified to homogeneity. Colony formation by the RT4 cell line, at 37 degrees, was decreased less than 10% with 200 units IFN-alpha per ml and 63% by 200 units IFN-beta per ml. At 39.5 degrees, colony formation by untreated RT4 cells was inhibited 48%. Treatment with IFN-beta at 39.5 degrees did not result in an enhancement of the antiproliferative effect; however, treatment with IFN-alpha enhanced the inhibition from less than 10% to 98%. These results suggest that a supraadditive relationship exists between antiproliferative effects of IFN and temperature elevation. The differences seen between IFN-alpha and IFN-beta may be due to the different stabilities of these two molecules. In order to probe the mechanism of the enhanced antiproliferative effect, activity of an IFN-induced enzyme, 2'-5'-oligoadenylate synthetase, was measured. IFN-alpha treatment resulted in significantly greater 2'-5'-oligoadenylate synthetase induction at 39.5 degrees than at 37 degrees. Thus, two cellular effects resulting from IFN were augmented by increased temperature.