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Sensitivity of Resistant Human Tumor Cell Lines to Tumor Necrosis Factor and Adriamycin Used in Combination: Correlation between Down-Regulation of Tumor Necrosis Factor-Messenger RNA Induction and Overcoming Resistance¹

Department of Microbiology and Immunology and Jonsson Comprehensive Cancer Center, University of California at Los Angeles School of Medicine, Los Angeles, California 90024

² To whom requests for reprints should be addressed, at University of California, Department of Microbiology and Immunology, 10833 Le Conte Avenue, Los Angeles, CA 90024-1747.

A number of human tumor cell lines of various histological origin were examined for their sensitivity and resistance to tumor necrosis factor- (TNF) and Adriamycin (ADR). Six ovarian lines, and one each of a renal, lung, and B-cell line, were tested for putative mechanisms of resistance to these agents. Cytotoxicity resulting from TNF or ADR showed no overall correlation in these lines. The combination of TNF and ADR produced enhanced cytotoxicity against these tumor lines and furthermore resulted in overcoming the resistance of TNF or ADR alone or in combination. A proposed mechanism of TNF resistance in tumor cells is the endogenous production of TNF mRNA and protein. There was a positive correlation between resistance to TNF and the constitutive production of TNF mRNA and protein. The TNF-resistant lines that did not constitutively produce TNF mRNA and protein and the three TNF-sensitive tumor lines exhibited up-regulation of their TNF mRNA in the presence of TNF or phorbol myristate acetate/ionophore, but did not secrete any detectable protein. Due to the enhanced cytotoxicity seen with the combination of TNF and ADR, the effect of this combination on the level of TNF mRNA was examined. ADR alone reduced the constitutive level of TNF mRNA and in combination with TNF reduced the level of induction produced by TNF. This down-regulation of TNF mRNA by ADR may play a role in the enhanced cytotoxicity seen with the combination of these 2 agents.

¹ This study received financial support from the Concern Foundation of Los Angeles, CA, and the Boiron Foundation of France.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/23/92. Accepted 9/16/92.

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