TNF-MEDIATED KILLING OF HUMAN LEUKEMIC-CELLS - EFFECTS OF ENDOGENOUS ANTIOXIDANT LEVELS AND TNF-ALPHA EXPRESSION IN LEUKEMIC-CELL LINES

Using the human erythroleukaemic cell line K562 cl.6 and its daunorubi cin-resistant subline K/DAU(600) and the human T-lymphoblastic leukaem ic cell line CCRF-CEM and its vinblastine-resistant subline CEM/VLB(10 0) we have shown that the drug-resistant cell lines were more sensitiv e to cytotoxicity induced by tumour necrosis factor-alpha (TNF alpha). Drug-resistant cell lines showed increased activities of copper/zinc superoxide dismutase (Cu/ZnSOD) and catalase compared with their paren tal drug-sensitive cell lines. However, the greater susceptibility of drug-resistant cells to TNF alpha cytotoxicity was, in part, related t o their decreased activities of manganese superoxide dismutase (MnSOD) . Persistence of this differential sensitivity when MnSOD is inhibited by sodium nitroprusside (SNP) suggests that the greater susceptibilit y of drug-resistant cells to TNF alpha was not entirely due to their d ecreased level of MnSOD activity. K562 cl.6 and K/DAU(600) which were more resistant to TNF alpha, both expressed greater levels of endogeno us plasma membrane-bound TNF alpha than the CCRF-CEM cell line. All ce ll lines examined were (more or less) equal in susceptibility to the c ytolytic effect of exogenous O-2(.-) generated by xanthine/xanthine ox idase. These results demonstrate that both MnSOD and endogenous TNF al pha play a role in protecting leukaemic cells against TNF alpha cytoto xicity, but there is an unknown mechanism that causes drug-resistant c ells to be more susceptible to TNF alpha cytotoxicity.