ANTI-FAS APO-1 MONOCLONAL-ANTIBODY CH-11 DEPLETES GLUTATHIONE AND KILLS MULTIDRUG-RESISTANT HUMAN LEUKEMIC-CELLS/

Apoptosis is a common pathway by which cells respond to noxious insult s or growth regulatory factors. Since cellular glutathione (GSH) conte nt has long been known to govern response to antineoplastic treatment we have compared induction of apoptosis in drug sensitive (HL-60 and K 562/WT) and drug resistant (KG-la and K562/ADM) human leukemic cell li nes by the monoclonal antibody CH-11 (anti-Fas/Apo-1). Fraction of apo ptotic cells and cellular GSH were determined by flow cytometry. All c ell lines were induced to undergo apoptosis by exposure to mAb CH-11 i ndependent of resistance to conventional antineoplastic treatment. In conjunction with exposure to daunorubicin, vincristine, carboplatin, c ytosine arabinoside, dexamethasone, or ionizing irradiation the effect of mAb CH-11 on induction of apoptosis was no more than additive. In contrast, preincubation with IFN-gamma markedly enhanced the induction of apoptosis by mAb CH-11 due to an increase of Fas-receptor expressi on. In each instance, GSH content decreased with increasing fraction o f apoptotic cells indicating a crucial role of GSH in the apoptotic pa thway.