Overcoming tumor necrosis factor and drug resistance of human tumor cell lines by combination treatment with anti-Fas antibody and drugs or toxins.
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-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 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 gamma-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.
Morimoto
H
H
Department of Microbiology and Immunology, UCLA School of Medicine, University of California 90024.
Yonehara
S
S
Bonavida
B
B
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000954:Antigens, Surface / Q000276:immunology*; D002945:Cisplatin / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000187:drug effects; D004167:Diphtheria Toxin / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use*; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000627:therapeutic use*; D012276:Ricin / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D004273:DNA, Neoplasm; D004167:Diphtheria Toxin; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004317:Doxorubicin; D007371:Interferon-gamma; D012276:Ricin; D002945:Cisplatin