Potentiation of the in vitro cytotoxicity of chlorambucil by monoclonal antibodies.
It had previously been shown by using polyclonal antibodies that chlorambucil (CBL) and antibody did not have to be covalently bound to selectively inhibit tumor cell growth. This paper has reexamined this phenomena by using monoclonal antibodies (MoAb) and has sought to determine how antibody may serve to focus and to increase the cytotoxic effect of non-covalently bound CBL. In vitro, it was shown that MoAb per se had no effect, the MoAb had to be reactive with and to bind to tumor target cells for CBL to have an enhanced cytotoxicity. Furthermore, not all MoAb were effective; IgM and IgG2a subclasses enhanced CBL cytotoxicity, but IgG3 did not. At the cell surface, studies clearly showed that endocytosis of CBL and MoAb did not occur, as metabolic inhibitors, and lowered temperatures, which both inhibit endocytosis, had no effect on their cytotoxicity. In addition, NH4Cl an inhibitor of lysosomal enzymes did not reduce the cytotoxicity of CBL and MoAb. Thus CBL that is non-covalently bound to MoAb enters the cell independently of the MoAb. We conclude therefore that cell-bound MoAb is able to concentrate CBL on the surface of tumor cells by an unknown mechanism thereby enabling CBL to selectively alkylate their cell membranes and subsequently inhibit additional tumor cell growth.
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000276:immunology*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000008:administration & dosage*; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D004705:Endocytosis; D007132:Immunoglobulin Isotypes / Q000276:immunology; D066298:In Vitro Techniques; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D013696:Temperature
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D007132:Immunoglobulin Isotypes; D000643:Ammonium Chloride; D002699:Chlorambucil