List A F
Section of Hematology/Oncology, Arizona Cancer Center, University of Arizona College of Medicine, Tucson 85724, USA.
Leukemia. 1996 Jun;10(6):937-42.
Cellular expression of the multidrug transporter, P-glycoprotein (Pgp) is recognized as a biological mechanism possibly contributing to treatment failure in acute myeloid leukemia (AML). Correlative studies indicate its association with poor risk features including secondary AML, CD34+ surface phenotype, unfavorable karyotype and advanced age. Reported disparity in the prognostic impact of Pgp relates in part to variance in drug transport capacity. In Pgp expressing cells, capacity for drug extrusion is governed by maturation phenotype and is largely restricted to CD34+ populations lacking myeloid maturation antigens. Three competitive inhibitors of Pgp function showing promise in pilot studies, cyclosporin A (CsA), quinine and the cyclosporin D analogue PSC 833, have entered testing in phase III trials. The presence of non-Pgp-related mechanisms of multidrug resistance, relatively insensitive to Pgp modulators, may limit the success of such treatment strategies. Preliminary investigations indicate that overexpression of the gene encoding the multidrug resistance-related protein (MRP) occurs infrequently in de novo AML, but relative increases in gene message are evident in relapsed specimens. Overexpression of lung resistance protein (LRP) is associated with adverse prognostic variables such as age, secondary disease and Pgp, and has demonstrated prognostic relevance. Because treatment with Pgp modulators may select for this drug resistance phenotype, LRP merits evaluation in randomized trials of Pgp antagonists. These observations indicate that multiple biological mechanisms contribute to anthracycline resistance in AML, thereby warranting development of multifunctional modulators or chemotherapeutic agents with novel mechanisms of action.
多药转运蛋白P-糖蛋白（Pgp）的细胞表达被认为是一种可能导致急性髓系白血病（AML）治疗失败的生物学机制。相关研究表明，它与不良风险特征相关，包括继发性AML、CD34+表面表型、不良核型和高龄。报道的Pgp预后影响的差异部分与药物转运能力的差异有关。在表达Pgp的细胞中，药物外排能力由成熟表型决定，并且在很大程度上仅限于缺乏髓系成熟抗原的CD34+群体。三种在初步研究中显示出前景的Pgp功能竞争性抑制剂，环孢素A（CsA）、奎宁和环孢素D类似物PSC 833，已进入III期试验测试。存在对Pgp调节剂相对不敏感的非Pgp相关多药耐药机制，可能会限制此类治疗策略的成功。初步研究表明，编码多药耐药相关蛋白（MRP）的基因在初发AML中很少过度表达，但在复发标本中基因信息相对增加很明显。肺耐药蛋白（LRP）的过度表达与年龄、继发性疾病和Pgp等不良预后变量相关，并已证明具有预后相关性。由于用Pgp调节剂治疗可能会选择这种耐药表型，因此LRP值得在Pgp拮抗剂的随机试验中进行评估。这些观察结果表明，多种生物学机制导致AML对蒽环类药物耐药，因此有必要开发具有新作用机制的多功能调节剂或化疗药物。
