The relationship between multi-drug resistance and resistance to natural-killer-cell and lymphokine-activated killer-cell lysis in human leukemic cell lines.
Results concerning a possible link between susceptibility to natural-cell-mediated immune cytolysis and the multi-drug resistance (MDR) phenotype are conflicting. We evaluated in human acute lymphocytic leukemia the relationship between acquired drug resistance and susceptibility to cytolysis mediated by endogenous, interferon-activated, and interleukin-2-activated natural cytotoxic cells. Eight human leukemia drug-resistant/sensitive cell line pairs were evaluated; drug-resistant sub-lines included those selected for primary resistance to adriamycin, etoposide, teniposide, vincristine, and vinblastine. A majority of P-glycoprotein-positive MDR sub-lines displayed slight but statistically significant resistance to endogenous and/or interferon-activated natural-killer(NK)-cell-mediated lysis, as compared with the drug-sensitive parental type. P-glycoprotein-negative sub-lines displayed variable NK susceptibility; within this group, the variants selected for primary etoposide resistance were more susceptible to NK cytolysis than parental cells. Results of cold-target-inhibition experiments suggest that altered NK susceptibility does not arise solely from modulation of NK target recognition and adherence structures. IL2-activated killer (LAK) cells lysed both drug-sensitive and drug-resistant lines. Two MDR lines selected for primary etoposide resistance displayed enhanced LAK susceptibility. In contrast, the 2 variants selected for resistance to adriamycin exhibited partial resistance to LAK-mediated killing, which could be overcome at high effector-to-target ratios. Our results support the development of interleukin-2/LAK immunotherapy for the treatment of leukemias with acquired drug resistance.
Treichel
R S
RS
Department of Biology, Oberlin College, OH 44074-1082.
Olken
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004351:Drug Resistance; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007372:Interferons / Q000494:pharmacology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy; D008562:Membrane Glycoproteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D007372:Interferons