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Modulation of the Growth of Transformed Cells by Human Tumor Necrosis Factor- and Interferon-

Departments of Pharmacological Sciences [G. D. L., B. J. S., H. M. S.] and Molecular Immunology [B. B. A., T. E. E.], Genentech, Inc., South San Francisco, California 94080

Recombinant human tumor necrosis factor- (rHuTNF-) inhibited growth of the cervical carcinoma cell line, ME-180^neo, at doses greater than 50 units/ml, but stimulated the growth of these cells at low doses (0.1–10 units/ml). ME-180^neo variants selected for resistance to the cytotoxic effects of rHuTNF- retained the ability to be growth stimulated at all concentrations tested. ME-180^neo cells and the rHuTNF--resistant ME-180^neo variants possessed equivalent steady state numbers of TNF- receptors with similar K_d values. Recombinant human interferon- (rHuIFN-) augmented the rHuTNF--induced cytotoxic response of ME-180^neo cells and overcame the resistance of the ME-180^neo variants to rHuTNF- cytotoxicity. In separate experiments we were able to show that the number of TNF- binding sites on both rHuTNF--sensitive and -resistant ME-180^neo cells was similar and was increased by treatment with rHuIFN-. These results suggest that the growth stimulation of tumor cells mediated by rHuTNF- can be dissociated from the cytotoxic response and that these responses are not related to the number or affinity of TNF- binding sites.

¹ To whom requests for reprints should be addressed, at Department of Pharmacological Sciences, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080.

² Present address: AMGEN, Thousand Oaks, CA 91320.

Received 8/ 8/86. Revised 4/15/87. Accepted 7/21/87.

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