Adriamycin-induced resistance to natural killer (NK)-mediated cytotoxicity

Studies were done to determine the susceptibility of a colon carcinoma cell line, LoVo, to natural killer (NK) mediated lysis after exposure to the tumor cells to Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH). LoVo cells were exposed to ADR (0.4 micrograms/ml) for various time intervals and then tested for sensitivity to lysis by NK cells from the peripheral blood of normal donors in a sodium chromate (Cr51) release cytotoxicity assay. Exposure of tumor targets to ADR induced a resistance to NK-mediated lysis. Susceptibility to lysis decreased progressively to approximately 60% of control levels after 72 hours of ADR exposure. The induction of resistance was dependent on ADR dose, but did not magnify with doses greater than 0.4 micrograms/ml. When target cells were allowed to recover from ADR in fresh medium for 48 hours, complete reversal of the ADR effect was seen. The effect of interleukin-2 (IL-2) stimulation on the NK lysis of LoVo also was tested. IL-2-stimulated effector cells demonstrated enhanced cytotoxicity to LoVo targets and were able to overcome the ADR-induced resistance to lysis. The mechanism of resistance does not appear to be related to the altered binding of effectors to chemotherapy-treated targets, as suggested by single cell assay results.