Arai Y, Masuda M, Sugawara I, Arai T, Motoji T, Tsuruo T, Oshimi K, Mizoguchi H
Department of Hematology, Tokyo Women's Medical College, Shinjuku-ku, Japan.
Leuk Res. 1997 Apr;21(4):313-9. doi: 10.1016/s0145-2126(96)00130-0.
We performed immunocytochemistry to detect mdr1 and mdr3 P-glycoproteins (P-gps) in 81 patients with acute and chronic leukemia, using the mdr1 P-gp-specific monoclonal antibody (MoAb) MRK16, and the mdr3 P-gp-specific MDR3M. Immunoreactivity for the mdr1 gene product was positive 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 lymphocytic leukemia (CLL) were mdr3 P-gp positive. Of the patients with granular-lymphocyte proliferative disorder (GLPD), a chronic T-cell or natural killer cell leukemia, 8/17 (47%) were positive for mdr1 P-gp and 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 intracellular rhodamine123 (Rh123) levels of mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells from patients with acute lymphocytic leukaemia, on the addition of 10 microM cyclosporin A (CyA). The addition of CyA led to significant increases in intracellular Rh123 levels in mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells. Results of the assay for dye efflux suggested that the mdr3 P-gp has a role in drug resistance, and functional drug-efflux capacity. In 31 acute leukemia patients at initial diagnosis, mdr1 or mdr3 P-gp expression correlated significantly to an outcome of complete remission (CR). In 54 acute leukemia patients, exposure to precytotoxic agents correlated significantly to expression, with a significant higher number of patients mdr1 or mdr3 P-gp positive than negative. In the 54 patients with acute leukemia, mdr1 P-gp expression correlated to mdr3 P-gp expression significantly (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 precytotoxic agents, nor did mdr1 P-gp expression correlate to mdr3 P-gp expression. It may be speculated that precytotoxic agents induced mdr1 and mdr3 P-gp expression in acute leukemia; however, in chronic leukemia, both P-gps were expressed independently of exposure to precytotoxic agents.
我们采用mdr1 P-糖蛋白（P-gp）特异性单克隆抗体（MoAb）MRK16和mdr3 P-gp特异性抗体MDR3M，对81例急性和慢性白血病患者进行免疫细胞化学检测，以检测mdr1和mdr3 P-糖蛋白（P-gps）。81例患者中，27例（33%）mdr1基因产物免疫反应呈阳性。81例患者中，20例（25%）抗mdr3 P-gp MoAb免疫反应呈阳性。54例急性白血病患者中，17例（31%）mdr1 P-gp呈阳性，8例（15%）mdr3 P-gp呈阳性。慢性淋巴细胞白血病（CLL）患者中，很大一部分（60%）mdr3 P-gp呈阳性。在颗粒淋巴细胞增殖性疾病（GLPD）患者中，一种慢性T细胞或自然杀伤细胞白血病，17例中有8例（47%）mdr1 P-gp呈阳性，17例中有6例（35%）mdr3 P-gp呈阳性。23例慢性白血病（CLL和GLPD）患者中，10例（37%）mdr1 P-gp呈阳性，12例（44%）mdr3 P-gp呈阳性。为阐明mdr3 P-gp的功能，我们检测了急性淋巴细胞白血病患者中mdr1 P-gp阴性和mdr3 P-gp阳性白血病细胞内罗丹明123（Rh123）水平，加入10微摩尔环孢素A（CyA）后进行检测。加入CyA后，mdr1 P-gp阴性和mdr3 P-gp阳性白血病细胞内Rh123水平显著升高。染料外排试验结果表明，mdr3 P-gp在耐药性及功能性药物外排能力方面发挥作用。31例初诊急性白血病患者中，mdr1或mdr3 P-gp表达与完全缓解（CR）结局显著相关。54例急性白血病患者中，接触细胞毒性前体药物与表达显著相关，mdr1或mdr3 P-gp阳性患者数量显著多于阴性患者。54例急性白血病患者中，mdr1 P-gp表达与mdr3 P-gp表达显著相关（p=0.0007）。27例慢性白血病（CLL和GLPD）患者中，mdr1和mdr3 P-gp表达与接触细胞毒性前体药物无关，mdr1 P-gp表达与mdr3 P-gp表达也无关。可以推测，细胞毒性前体药物诱导急性白血病中mdr1和mdr3 P-gp表达；然而，在慢性白血病中，两种P-gps的表达与接触细胞毒性前体药物无关。
