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Overcoming Tumor Necrosis Factor and Drug Resistance of Human Tumor Cell Lines by Combination Treatment with Anti-Fas Antibody and Drugs or Toxins¹

Department of Microbiology and Immunology and the Jonsson Comprehensive Cancer Center, UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California 90024 [H. M., B. B.], and the Biotechnology Institute, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [S. Y.]

Monoclonal mouse anti-Fas antibody is directed against Fas antigen, a M_r 36,000 encoded polypeptide that belongs to the family of cell surface proteins which includes nerve growth factor receptor, tumor necrosis factor (TNF) receptors, B-cell antigen CD40, and T-cell antigens OX40. Anti-Fas antibody mimics TNF- in its cytolytic activity but not in other TNF--mediated activities. Thus, we examined if anti-Fas antibody synergizes in cytotoxicity with toxins and drugs. The present studies demonstrate that anti-Fas antibody in combination with diphtheria toxin (DTX), Adriamycin, or cis-platinum results in enhanced cytotoxicity and synergy and also overrides resistance to TNF, drugs, or toxins when tested against a battery of human tumor cell lines. Synergy with anti-Fas and DTX requires that DTX is enzymatically active, since inhibitors of DTX-mediated protein synthesis inhibition resulted in loss of synergy. When the plant toxin ricin was used, there was no synergy with anti-Fas antibody but rather an additive effect. The synergy was not obtained in a TNF receptor-negative line but was achieved with other anti-Fas-resistant lines. Cell lines resistant to either Adriamycin or cis-platinum were rendered sensitive by the combination of drug and anti-Fas antibody. Further, combination treatment of anti-Fas and Adriamycin overcame resistance of the gp 170-expressing, multidrug-resistant MDR ovarian line. In all cases, cytotoxicity was augmented by pretreatment of target cells with -interferon which upregulates Fas antigen expression. These results show that anti-Fas antibody can synergize in cytotoxicity with toxins and chemotherapeutic drugs, and combination treatment can reverse resistance to TNF, toxins, and/or drugs.

¹ This work was supported in part by a grant from Institut Henri Beaufour, France.

² To whom requests for reprints should be addressed, at Department of Microbiology and Immunology UCLA School of Medicine, Los Angeles, CA 90024.

Received 11/ 9/92. Accepted 3/25/93.

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