In vitro synergistic effects of natural human tumor necrosis factor and natural human interferon-alpha.

Tumor necrosis factor and interferons are multifunctional cytokines. The present studies were undertaken to investigate the biologic interactions of highly purified natural human tumor necrosis factor and highly purified natural human interferon-alpha, which were derived from a B cell acute lymphatic leukemia line (BALL-1 cells) sensitized with hemagglutinating virus of Japan (HVJ). Combined treatment with natural human tumor necrosis factor and natural human interferon-alpha synergistically inhibited the in vitro proliferation of P4788 cells derived from a human colon cancer. Flow cytometric analysis of the cell cycle of asynchronous cells indicated that target cells treated with natural human tumor necrosis factor alone accumulate in the S phase. This accumulation in the S phase of the cell cycle was augmented by combined treatment with natural human tumor necrosis factor and natural human interferon-alpha. The growth inhibitions appeared to be a result of arrest in the S phase of the cell cycle. Combined treatment with these cytokines had potent cytostatic and cytotoxic effects on most of the tested malignant cell lines of human epithelial origin.