EXPRESSION OF THE MDR1 AND MDR3 GENE-PRODUCTS IN ACUTE AND CHRONIC LEUKEMIAS

We performed immunocytochemistry to detect mdr1 and mdr3 P-glycoprotei ns (P-gps) in 81 patients with acute and chronic leukemia, using the m dr1 P-gp-specific monoclonal antibody (MoAb) MRK16, and the rrdr3 P-gp -specific MDR3M. Immunoreactivity for the mdr1 gene product was positi ve in 27 out of 81 (33%) patients. Immunoreactivity with the anti-mdr3 P-gp MoAb was positive in 20 out of 81 (25%) patients. Of 54 patients with acute leukemia, 17 (31%) were positive for mdr1 P-gp and 8 (15%) for mdr3 P-gp. A high proportion (60%) of patients with chronic lymph ocytic leukemia (CLL) were mdr3 P-gp positive. Of the patients with gr anular-lymphocyte proliferative disorder (GLPD), a chronic T-cell or n atural killer cell leukemia, 8/17 (47%) were positive for mdr1 P-gp an d 6/17 (35%) for mdr3 P-gp. Of 23 patients with chronic leukemia (CLL and GLPD), 10 (37%) were positive for mdr1 P-gp and 12 (44%) for mdr3 P-gp. To clarify the function of the mdr3 P-gp, we examined the intrac ellular rhodamine123 (Rh123) levels of mdr1 P-gp-negative and mdr3 P-g p-positive leukemic cells from patients with acute lymphocytic leukaem ia, on the addition of 10 mu M cyclosporin A (CyA). The addition of Cy A led to significant increases in intracellular Rh123 levels in mdr1 P -gp-negative and mdr3 P-gp-positive leukemic cells. Results of the ass ay for dye efflux suggested that the mdr3 P-gp has a role in drug resi stance, and functional drug-efflux capacity. In 31 acute leukemia pati ents at initial diagnosis, mdr1 or mdr3 P-gp expression correlated sig nificantly to an outcome of complete remission (CR). In 54 acute leuke mia patients, exposure to precytotoxic agents correlated significantly to expression, with a significant higher number of patients mdr1 or m dr3 P-gp positive than negative. In the 54 patients with acute leukemi a, mdr1 P-gp expression correlated to mdr3 P-gp expression significant ly (p=0.0007). In the 27 patients with chronic leukemia (CLL and GLPD) , mdr1 and mdr3 P-gp expression did not correlate to exposure to precy totoxic agents, nor did mdr1 P-gp expression correlate to mdr3 P-gp ex pression. It may be speculated that precytotoxic agents induced mdr1 a nd mdr3 P-gp expression in acute leukemia; however, in chronic leukemi a, both P-gps were expressed independently of exposure to precytotoxic agents. (C) 1997 Elsevier Science Ltd.