DRUG-INDUCED APOPTOSIS IS ASSOCIATED WITH ENHANCED FAS (APO-1 CD95) LIGAND EXPRESSION BUT OCCURS INDEPENDENTLY OF FAS (APO-1/CD95) SIGNALING IN HUMAN T-ACUTE LYMPHATIC-LEUKEMIA CELLS/

Induction of apoptosis is considered to be the underlying mechanism th at accounts for the efficiency of chemotherapeutic drugs. It has recen tly been proposed that induction of Fas ligand (FasL) expression with subsequent autocrine and/or paracrine induction of cell death through binding to the Fas (Apo-1/CD95) membrane accounts for chemotherapy-ass ociated apoptosis. In the present study, me analyzed the significance of Fast expression in the mediation of drug-induced apoptosis in the T -acute lymphatic leukemia model CEM. In particular, me examined the po tential of the tumor drugs fludarabine, doxorubicin, and cisplatin to induce FasL expression. We also raised the question of whether apoptos is induced by these drugs occurs through the Fas pathway and hence can be blocked by the cowpox virus protein CrmA, a specific inhibitor of this pathway, All tumor drugs examined led to an increase in FasL prot ein. However, overexpression of CrmA had no effect on drug-induced apo ptosis. Moreover, neither incubation with inhibitory monoclonal antibo dies against Fas that completely prevented Fas-induced apoptosis in th ese cells nor pretreatment with a monoclonal antibody to FasL affected drug-induced cell death, Our observations suggest a Fas/FasL-independ ent mechanism for drug-induced apoptosis and exclude the involvement o f caspase 1 and caspase 8 in this process in T-acute lymphatic leukemi a cells.