Prevention of resistance to IFN-alpha antiproliferative activity: characterization of the effect of IFN-gamma and substitution for IFN-gamma by tumor necrosis factor.

Non-genetic resistance to the antiproliferative effects of interferon-alpha (IFN-alpha) develops in murine and human melanoma cells within 2-4 days of exposure of the cells to IFN-alpha. Simultaneous treatment of murine B16 melanoma cells with MuIFN-gamma and MuIFN-alpha prevents the development of resistance. In this study, the ability of MuIFN-gamma pretreatment to prevent the development of resistance was assessed for varying concentrations of MuIFN-gamma and for varying lengths of time of pretreatment. Pretreatment of the cells for 48 h with MuIFN-gamma using concentrations as low as 5 U/ml prevents the subsequent development of resistance when the cells are cloned in the presence of MuIFN-alpha. Higher concentrations of MuIFN-gamma are more effective in preventing the development of resistance. In addition, short MuIFN-gamma pretreatment times, such as 2-4 h, appeared to be most effective in preventing the development of resistance. In order to determine the mechanism for this biological effect, various second messenger perturbing chemical agents and several other biological agents were screened for ability to prevent the development of resistance. Neither interleukin-2 (IL-2), epidermal growth factor (EGF), nor any of the chemical agents examined could prevent the development of resistance, nor did they alter the ability of MuIFN-gamma to prevent the development of resistance. Tumor necrosis factor (TNF), however, was able to substitute for MuIFN-gamma in preventing the development of resistance, using concentrations of 125 ng/ml and higher.(ABSTRACT TRUNCATED AT 250 WORDS)