Somatic cell mutants resistant to ricin, diphtheria toxin, and to immunotoxins.
The human B-cell line Namalwa expresses the common acute lymphoblastic leukemia antigen (CALLA). Frame-shift mutants in Namalwa cell cultures were generated with ICR-191, and mutants were then selected for resistance to ricin or resistance to a conjugate of ricin with the anti-CALLA antibody J5 in the presence of lactose. Three mutants were found that were resistant to ricin and were in addition shown to be resistant to diphtheria toxin, to a J5-ricin conjugate, and to a conjugate between ricin B-chain and gelonin. The mutants, however, were sensitive to a J5-gelonin conjugate. These mutants expressed high levels of CALLA and/or receptors for ricin, and their cell-free translation systems appeared to be as sensitive to the inhibitory action of ricin A-chain and of gelonin as the translation system of wild-type Namalwa cells. The behavior of these mutants was consistent with the hypothesis that these cells possess an alteration of their surface that impedes the passage of ricin and diphtheria toxin across the plasma membrane. A fourth mutant was found to bind reduced quantities of ricin and was resistant to ricin but was sensitive to J5-ricin. The properties of this cell line provide evidence that the binding of antibody-ricin conjugates to cells via the ricin moiety may be prevented without impeding the cytotoxicity of the conjugates.
D000951:Antigens, Neoplasm / Q000032:analysis; D002460:Cell Line; D002470:Cell Survival; D004167:Diphtheria Toxin / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004705:Endocytosis; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007945:Leukemia, Lymphoid / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D015260:Neprilysin; D010447:Peptide Hydrolases / Q000378:metabolism; D011975:Receptors, Mitogen / Q000378:metabolism; D012276:Ricin / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D000951:Antigens, Neoplasm; D004167:Diphtheria Toxin; D000922:Immunotoxins; D011975:Receptors, Mitogen; C032650:Ricinus communis lectin receptor; D013438:Sulfhydryl Compounds; D012276:Ricin; D010447:Peptide Hydrolases; D015260:Neprilysin