Potentiation of a weakly active ricin A chain immunotoxin recognizing the neural cell adhesion molecule.
A ricin A chain immunotoxin, SEN36-ricin A chain, directed against the neural cell adhesion molecule (N-CAM) had no selective cytotoxic activity against three different small cell lung cancer (SCLC) cell lines in tissue culture despite expression of the target antigen on more than 98% of cells in each line detected by indirect immunofluorescence. Treatment of the SW2 SCLC cell line with suramin and interferons alpha and gamma increased the level of N-CAM expression only slightly and had no significant effect on the cytotoxic activity of the SEN36 immunotoxin. In the presence of the carboxylic ionophore monensin at a concentration of 0.1 microM, the toxicity of SEN36-ricin A chain to the SW2 cell line was enhanced by 12,000-fold. In contrast, lysosomotropic amines showed little or no potentiation of activity, suggesting that lysosomal degradation was not the major factor limiting the action of the anti-N-CAM immunotoxin. The findings of this study indicate that ricin A chain immunotoxins directed against N-CAM on SCLC are unlikely to have sufficient activity to be useful therapeutic agents in the absence of potentiating agents such as monensin, which can interfere with the normal intracellular pathways of antigen routing.
Derbyshire
E J
EJ
Drug Targeting Laboratory, Section of Immunology, Institute of Cancer Research, Sutton, UK.
Stahel
R A
RA
Wawrzynczak
E J
EJ
D018288:Carcinoma, Small Cell / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000276:immunology*; D008175:Lung Neoplasms / Q000473:pathology; D046911:Macromolecular Substances; D008985:Monensin / Q000494:pharmacology; D012276:Ricin / Q000276:immunology*; D014407:Tumor Cells, Cultured
D015816:Cell Adhesion Molecules, Neuronal; D000922:Immunotoxins; D046911:Macromolecular Substances; D012276:Ricin; D008985:Monensin