Beutler, E. - BCMD: The First Year. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Efferth, T., Fabry, U., Osieka, R. - Anti-Fas/Apo-1 Monoclonal Antibody CH-11 Depletes Glutathione and Kills Multidrug-Resistant Human Leukemic Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2-9

ABSTRACT. Apoptosis is a common pathway by which cells respond to noxious insults or growth regulatory factors. Since cellular glutathione (GSH) content has long been known to govern response to antineoplastic treatment we have compared induction of apoptosis in drug sensitive (HL-60 and K562/WT) and drug resistant (KG-1a and K562/ADM) human leukemic cell lines by the monoclonal antibody CH-11 (anti-Fas/Apo-1). Fraction of apoptotic cells and cellular GSH were determined by flow cytometry. All cell lines were induced to undergo apoptosis by exposure to mAb CH-11 independent of resistance to conventional antineoplastic treatment. In conjunction with exposure to daunorubicin, vincristine, carboplatin, cytosine 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 expression. In each instance, GSH content decreased with increasing fraction of apoptotic cells indicating a crucial role of GSH in the apoptotic pathway.

Keywords: apoptosis, Fas/APO-1, glutathione, drug resistance, leukemia.

Reprint requests to: Professor Dr. R. Osieka, Medizinische Klinik IV der RWTH Aachen, PauwelsstraBe 30, 52057 Aachen, Germany, phone 0241/8089805, fax 0241/8888449.

Communicated on January 18, 1996 by R.A. Gottlieb, M.D., Department of Molecular and Experimental Medicine, Division of Biochemistry, The Scripps Research Institute, 10666 N. Torrey Pines Rd., NX7, La Jolla, California USA 92037.