Calicheamicin-conjugated humanized anti-CD33 monoclonal antibody (gemtuzumab zogamicin, CMA-676) shows cytocidal effect on CD33-positive leukemia cell lines, but is inactive on P-glycoprotein-expressing sublines

Calicheamicin-conjugated humanized anti-CD33 mouse monoclonal antibody, CMA -676, has recently been introduced to clinics as a promising drug to treat patients with acute myeloid leukemia (AML) in relapse. However, the mechani sm of action of CMA-676 has not been well elucidated. The cytotoxic effect of CMA-676 on HL60, NOMO-1, NB4, NKM-1, K562, Daudi, and the multidrug-resi stant sublines, NOMO-1/ADR and NB4/MDR, was investigated by cell cycle dist ribution and morphology. These studies were done by a video-microscopic sys tem, DNA fragmentation, dye exclusion and H-3-thymidine uptake after analys is of CD33, CD34, P-glycoprotein (P-gp), multidrug resistance (MDR)-associa ted protein and lung-related protein on these cells. A dose-dependent, sele ctive cytotoxic effect of CMA-676 was observed in cell lines that expressed CD33, and was dependent on the amount of CD33 and the proliferative speed of the cells. Sensitive cells were temporally arrested at the G2/M phase be fore undergoing morphological changes. CMA-676 is not effective on P-gp-exp ressing multidrug-resistant sublines compared with parental cell lines. MDR modifiers, MS209 and PSC833, restored the cytotoxic effect of CMA-676 in P -gp-expressing sublines. CMA-676 is a promising agent in the treatment of p atients with AML that expresses CD33. The combined use of CMA-676 and MDR m odifiers may increase the selective cytotoxic effect in multidrug-resistant AML.