SUSCEPTIBILITY TO LAK-MEDIATED CYTOTOXICITY OF MULTIDRUG-RESISTANT VARIANTS OF THE HUMAN RAJI CELL-LINE IS NOT RELATED TO EXPRESSION OF MAJOR CELLULAR ADHESION MOLECULES

The association of multidrug resistance (MDR) with resistance to lysis by natural killer (NK) and lymphokine-activated killer (LAK) cells is controversial. To address this issue further, drug-resistant variants of a human Burkitt lymphoma cell line (RAJI) were developed in vitro by intermittent exposure to Adriamycin(R) (R/ADR) or to etoposide (R/V P-16). The RAJI cell line was selected because it si a standard LAK-su sceptible target. Both MDR lines as well as the parent cell line were found to be resistant to NK-mediated lysis, but highly susceptible to LAK-mediated lysis. Notably, R/ADR cells, which express high levels of P-glycoprotein (P-gp), were nearly eight-times more susceptible to LA K-mediated lysis than parental cells, whereas R/VP-16 cells, which are P-gp-negative, were equally as susceptible as parental cells. Immunof luorescence analyses revealed that expression of cellular adhesion mol ecules that have been reported to control susceptibility of targets to NK- and LAK-lysis (ICAM-1, LFA-1, LFA-3, and MHC class I) did not dif fer significantly between the RAJI parent line and drug resistant vari ants. This finding suggests that the increased LAK-sensitivity of R/AD R results from alterations which affect post-binding stages of the LAK lytic pathway.