OVERCOMING TUMOR-NECROSIS-FACTOR AND DRUG-RESISTANCE OF HUMAN TUMOR-CELL LINES BY COMBINATION TREATMENT WITH ANTI-FAS ANTIBODY AND DRUGS ORTOXINS

Monoclonal mouse anti-Fas antibody is directed against Fas antigen, a M(r) 36,000 encoded polypeptide that belongs to the family of cell sur face proteins which includes nerve growth factor receptor, tumor necro sis factor (TNF) receptors, B-cell antigen CD40, and T-cell antigens O X40. Anti-Fas antibody mimics TNF-alpha in its cytolytic activity but not in other TNF-alpha-mediated activities. Thus, we examined if anti- Fas antibody synergizes in cytotoxicity with toxins and drugs. The pre sent studies demonstrate that anti-Fas antibody in combination with di phtheria 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. Syn ergy 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 syn ergy was not obtained in a TNF receptor-negative line but was achieved with other anti-Fas-resistant lines. Cell lines resistant to either A driamycin or cis-platinum were rendered sensitive by the combination o f drug and anti-Fas antibody. Further, combination treatment of anti-F as and Adriamycin overcame resistance of the gp 170-expressing, multid rug-resistant MDR ovarian line. In all cases, cytotoxicity was augment ed by pretreatment of target cells with gamma-interferon which upregul ates 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.