INVOLVEMENT OF THE CD95 (APO-1 FAS) RECEPTOR/LIGAND SYSTEM IN DRUG-INDUCED APOPTOSIS IN LEUKEMIA-CELLS/

Cytotoxic drugs used in chemotherapy of leukemias and solid tumors cau se apoptosis in target cells(1,2). In lymphoid cells the CD95 (APO-1/F as)/CD95 ligand (CD95-L) system is a key regulator of apoptosis(3-6). Here we describe that doxorbicin induces apoptosis via the CD95/CD95-L system in human leukemia T-cell lines. Doxorubicin-induced apoptosis was completely blocked by inhibition of gene expression and protein sy nthesis. Also, doxorbicin strongly stimulated CD95-L messenger RNA exp ression in vitro at concentrations relevant for therapy in vivo. CEM a nd jurkat cells resistant to CD95-mediated apoptosis were also resista nt to doxorbicin-induced apoptosis. Furthermore, doxorbicin-induced ap optosis was inhibited by blocking F(ab')(2)anti-APO-1 (anti-CD95) anti body fragments; Expression of CD95-L mRNA and protein in vitro was als o stimulated by other cytotoxic drugs such as methotrexate. The findin g that apoptosis caused by anticancer drugs may be mediated via the CD 95 system provides a new molecular insight into resistance and sensiti vity toward chemotherapy in malignancies.