Enhancement of the cytotoxic effect of anti-carcinoembryonic antigen immunotoxins by adenovirus and carboxylic ionophores.
Immunotoxins (monoclonal antibodies-ricin A-chain conjugates) directed against the tumor-associated antigen carcinoembryonic antigen (CEA) are selective in vitro cytotoxins for human adenocarcinoma cells. However, the kinetics of intoxication are relatively slow. The effects of the UV radiation-inactivated human adenovirus and the carboxylic ionophores monensin and nigericin were examined on immunotoxin cytotoxicity to the human colorectal adenocarcinoma cell line LoVo. In a 16-hour cytotoxicity assay, adenovirus reduced 33-fold the median inhibitory concentration from 3 X 10(-8) M to 9 X 10(-10) M. In timed cytotoxicity assays, 50% of control protein synthesis was reached in immunotoxin-treated cells twentyfold faster in the presence of adenovirus (0.5 hr) than in its absence (10 hr). Adenovirus produced no enhancement of immunotoxin effect on a control cell line or on a control immunotoxin on LoVo cells, demonstrating specificity of adenovirus effect. In addition, specific immunotoxin constructed with a nonreducible thioether bond, alone or with adenovirus, produced no toxicity on LoVo cells. These results suggest that both cell surface binding and presence of a reducible disulfide bond in the conjugate are necessary for adenovirus effect. Similar potentiation of the cytotoxicity of anti-CEA immunotoxins was produced by monensin and nigericin. These studies demonstrate that both adenovirus and carboxylic ionophores are potentiators of immunotoxins directed against the CEA, producing cytotoxicity equivalent to that of ricin but specific for CEA-positive adenocarcinoma cells in culture.
D000230:Adenocarcinoma / Q000473:pathology; D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007476:Ionophores / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D051379:Mice
D000911:Antibodies, Monoclonal; D002272:Carcinoembryonic Antigen; D000922:Immunotoxins; D007476:Ionophores