An anti-mucin immunotoxin BrE-3-ricin A-chain is potently and selectively toxic to human small-cell lung cancer.
Monoclonal antibodies (MAbs) known to recognize epithelial mucin or defined carbohydrate structures present on mucin molecules were screened for their ability to form cytotoxic agents with ricin A-chain active against human small-cell lung cancer (SCLC) in an indirect assay of immunotoxin cytotoxicity. Anti-X hapten and anti-Y hapten antibodies binding to a high proportion of SCLC cells mediated only weak to moderate effects on 3H-leucine incorporation in combination with the screening agent, sheep anti-mouse IgG F'ab-ricin A-chain. In contrast, the mouse MAb BrE-3, recognizing the polypeptide core of the MUCI mucin gene product, exerted potent and selective cytotoxic effects in the assay. An immunotoxin made by the direct attachment of ricin A-chain to BrE-3 was selectively toxic to SCLC cell lines in tissue culture. The cytotoxic activity of BrE-3-ricin A-chain was enhanced 100-fold in the presence of monensin but not by lysosomotropic amines or calcium antagonists. Our findings suggest that anti-mucin immunotoxins may have a therapeutic role to play in the treatment of SCLC.
Derbyshire
E J
EJ
Drug Targeting Laboratory, Institute of Cancer Research, Sutton, Surrey, UK.
Wawrzynczak
E J
EJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018288:Carcinoma, Small Cell / Q000473:pathology* / Q000628:therapy; D005455:Fluorescent Antibody Technique; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology* / Q000628:therapy; D051379:Mice; D009077:Mucins / Q000276:immunology*; D012276:Ricin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D009077:Mucins; D012276:Ricin