Lepelley P, Soenen V, Preudhomme C, Lai J L, Cosson A, Fenaux P
Laboratoire d'Hématologie A, Centre Hospitalier Universitaire de Lille, France.
Leukemia. 1994 Jun;8(6):998-1004.
Expression of P-glycoprotein (PGP), the product of the multi-drug resistance mdr1 gene was studied by immunocytochemistry on bone marrow slides using JSB1 monoclonal antibody and the alkaline phosphatase-antialkaline phosphatase (APAAP) and avidin-biotin-peroxidase (ABC) techniques in 82 cases of untreated myelodysplastic syndromes (MDS), of whom ten had evolved to AML (MDS-AML). The relationship between PGP expression, myeloperoxidase activity and immunophenotype of blast cells, karyotype and outcome was also analyzed. PGP expression was found in the blasts of 34 of the 82 patients (41%), the majority of blasts being stained in positive cases. PGP positivity was rare in 'low risk' MDS (RA and RARS: 2/12 cases) as opposed to 'high risk' MDS (RAEB, RAEB-T, CMML: 25/60 cases) and MDS-AML (7/10 cases) (p = 0.04). PGP expression was positively correlated to the presence of myeloperoxidase activity in less than 3% of blasts (p = 0.025), and CD34 antigen expression (p = 0.04), whereas CD33 antigen expression had borderline significance (p = 0.07), demonstrating that PGP expression predominated in blasts with an immature phenotype. An abnormal karyotype, and especially the presence of monosomy 7, was not correlated to a higher incidence of PGP expression, however. There was a trend for more frequent progression to AML and for shorter survival in PGP-positive cases, but differences with PGP-negative cases were not significant. Twenty patients received intensive anthracycline-Ara-C chemotherapy and ten (50%) achieved complete response, including 9/13 (69%) PGP-negative cases and 1/7 (14%) PGP-positive cases (p = 0.03). Twenty other patients were treated with low-dose Ara-C and ten (50%) responded (complete or partial response). PGP-positivity did not negatively affect response to low-dose Ara-C: 4/11 responses in PGP-negative, and 6/9 responses in PGP-positive patients (p = 0.18). Because the treatment choice in advanced MDS (especially between anthracycline-Ara-C or low-dose Ara-C, chemotherapy) is difficult, our preliminary therapeutic results suggest that the analysis of PGP expression could have practical importance in MDS. These findings however, will have to be confirmed on larger numbers of patients. Clinical trials using drugs potentially reverting mdr, activity could also be warranted in MDS.
采用免疫细胞化学方法，运用JSB1单克隆抗体以及碱性磷酸酶-抗碱性磷酸酶（APAAP）和抗生物素蛋白-生物素-过氧化物酶（ABC）技术，在82例未经治疗的骨髓增生异常综合征（MDS）患者的骨髓涂片上研究了多药耐药mdr1基因产物P-糖蛋白（PGP）的表达情况。其中10例已演变为急性髓系白血病（MDS-AML）。同时分析了PGP表达、髓过氧化物酶活性与原始细胞免疫表型、核型及预后之间的关系。82例患者中有34例（41%）的原始细胞中发现有PGP表达，在阳性病例中大多数原始细胞被染色。“低危”MDS（难治性贫血和难治性贫血伴环形铁粒幼细胞增多：2/12例）中PGP阳性少见，而“高危”MDS（难治性贫血伴原始细胞增多、难治性贫血伴原始细胞增多-转变型、慢性粒-单核细胞白血病：25/60例）和MDS-AML（7/10例）中PGP阳性较多（p = 0.04）。PGP表达与原始细胞中髓过氧化物酶活性低于3%（p = 0.025）以及CD34抗原表达（p = 0.04）呈正相关，而CD33抗原表达具有临界显著性（p = 0.07），表明PGP表达在具有未成熟表型的原始细胞中占主导。然而，异常核型，尤其是7号染色体单体的存在与PGP表达的较高发生率无关。PGP阳性病例有更频繁进展为AML的趋势以及生存期较短，但与PGP阴性病例的差异不显著。20例患者接受了强化蒽环类药物-阿糖胞苷化疗，10例（50%）获得完全缓解，其中包括13例PGP阴性病例中的9例（69%）和7例PGP阳性病例中的1例（14%）（p = 0.03）。另外20例患者接受了小剂量阿糖胞苷治疗，10例（50%）有反应（完全或部分缓解）。PGP阳性对小剂量阿糖胞苷的反应没有负面影响：PGP阴性患者中有4/11例有反应，PGP阳性患者中有6/9例有反应（p = 0.18）。由于晚期MDS的治疗选择（尤其是在蒽环类药物-阿糖胞苷或小剂量阿糖胞苷化疗之间）很困难，我们的初步治疗结果表明，PGP表达分析在MDS中可能具有实际意义。然而，这些发现必须在更多患者中得到证实。在MDS中也可能有必要进行使用可能逆转mdr活性药物的临床试验。
