Potent cytotoxic action of the immunotoxin SWA11-ricin A chain against human small cell lung cancer cell lines.
The cytotoxic activity profile of an immunotoxin, SWA11-ricin A chain, recognising a cell-surface antigen associated with human small cell lung cancer (SCLC), was examined in detail using a panel of SCLC, non-SCLC and non lung tumour cell lines in tissue culture. SWA11-ricin A chain was potently and selectively active against three SCLC cell lines of both classic and variant morphologies, inhibiting the incorporation of 3H-leucine with an IC50 of 5 x 10(-11) M. At a concentration of 1 x 10(-8) M, the SWA11 immunotoxin could selectively eliminate in excess of 99.9% of clonogenic tumour cells. Intoxication proceeded rapidly following a 4 h lag phase; the initial rate of protein synthesis inhibition occurred with a t50 of 2 h and a t10 of 7 h. The cytotoxic activity of SWA11-ricin A chain was potentiated by 100-fold in the presence of the carboxylic ionophore monensin at 1 x 10(-7) M. Kinetic studies revealed that monensin enhanced the rate of protein synthesis inhibition by two-fold and eliminated the lag phase suggesting a rapid effect on either the rate or route of internalisation. Studies with SWA11 could detect no influence of monensin on the rate of antibody internalisation and a transient delay in the delivery of internalised antibody to lysosomes was observed by immunoelectron microscopy.
Derbyshire
E J
EJ
Section of Immunology, Institute of Cancer Research, Sutton, Surrey, UK.
Henry
R V
RV
Stahel
R A
RA
Wawrzynczak
E J
EJ
D000911:Antibodies, Monoclonal / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000628:therapy*; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000628:therapy*; D004357:Drug Synergism; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000378:metabolism / Q000628:therapy*; D016253:Microscopy, Immunoelectron; D008985:Monensin / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D012276:Ricin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D009363:Neoplasm Proteins; D012276:Ricin; D008985:Monensin