Interferon sensitive and insensitive MHC variants of a murine thymoma differentially resistant to methotrexate-containing antibody-directed liposomes and immunotoxin.
We evaluated the ability of methotrexate-containing liposomes or a ricin alpha-chain immunotoxin, both associated with monoclonal antibodies specific for the major histocompatibility complex-encoded class I molecule H-2Kk, to kill cells of the murine k haplotype thymoma RDM4. Cells were incubated with liposomes or immunotoxin in the presence or absence of interferon-gamma, which is known to augment the expression of the target class I molecules. The great majority of cells were killed by either of these reagents. Two types of mutant cells were obtained: type 1 cells, selected by methotrexate-containing liposomes, failed to express sufficient target H-2k molecules to be killed by liposomes in the absence of interferon-gamma. In the presence of interferon-gamma, these cells increased expression of all H-2 class I molecules and could be killed by targeted liposomes. Type 2 cells were immunoselected from cloned type 1 cells by liposomes in the presence of interferon. These cells failed to respond to interferon with expression of the H-2Kk molecule, but continued to augment H-2Dk expression in response to interferon. A third variant (type 3) selected from the wild type population by an H-2Kk specific immunotoxin in the absence of interferon phenotypically resembled type 1 cells. Type 1 but not type 2 cells respond to interferon by augmented synthesis of H-2Kk specific mRNA. The results suggest that for interferon-sensitive cell surface molecules of tumor cells, use of interferon improves the efficacy of targeted chemotherapy, but does not prevent development of mutants lacking the target molecule.
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Machy
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Arnold
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Leserman
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D000954:Antigens, Surface / Q000032:analysis; D000939:Epitopes / Q000276:immunology; D014644:Genetic Variation; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D064532:Histocompatibility Antigen H-2D; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology*; D008081:Liposomes / Q000276:immunology* / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D012313:RNA / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000032:analysis; D017471:Receptors, Interferon; D012276:Ricin / Q000633:toxicity*; D018800:Thy-1 Antigens; D013945:Thymoma / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000939:Epitopes; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D008081:Liposomes; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D018800:Thy-1 Antigens; D012313:RNA; D007371:Interferon-gamma; D012276:Ricin; D008727:Methotrexate