Willman C L
UNM Center for Molecular and Cellular Diagnostics, University of New Mexico Cancer Center, Albuquerque 87131, USA.
Semin Hematol. 1997 Oct;34(4 Suppl 5):25-33.
Resistance to chemotherapy is a major obstacle in the treatment of patients with acute myeloid leukemia (AML). The majority of AML patients are intrinsically resistant to chemotherapy at initial diagnosis before chemotherapeutic exposure; such intrinsic resistance frequently results from expression of the multidrug resistance gene (MDR-1), which encodes a membrane transporter protein, P-glycoprotein (P-gp), that mediates drug efflux in leukemic cells. Expression of novel transporter proteins that confer alternative forms of multidrug resistance (MDR), such as the lung-resistance protein (LRP) and the MDR-associated protein (MRP), occurs more frequently in leukemic patients at relapse. Preliminary studies indicate that these proteins may also confer therapeutic resistance in leukemia. In patients older than 55 years of age, AML is characterized by a high frequency of unfavorable cytogenetics, P-gp expression, and functional drug efflux, which contribute to poor clinical outcome. In a multivariate analysis, secondary AML, unfavorable cytogenetics, and P-gp expression/function were each significantly and independently associated with a lower complete remission (CR) rate. Resistant disease was associated with P-gp expression and unfavorable cytogenetics. Strikingly, elderly patients with P-gp- de novo AML and favorable or intermediate cytogenetics had a CR rate of 81%. Patients with P-gp+ secondary AML with unfavorable cytogenetics had a CR rate of only 12%. Therefore, characterization of elderly AML patients at diagnosis using biologic parameters may help identify those patients who are likely to achieve a CR with conventional regimens, as well as those patients who require alternate treatment designed to overcome MDR. In contrast, expression of P-gp and functional drug efflux is detected in only 25% to 30% of AML patients less than 50 years of age. While P-gp expression is less strongly associated with a poor outcome in younger versus older AML patients, it remains strongly associated with resistant disease. Studies are ongoing to determine the prognostic significance of LRP and MRP in various forms of leukemia.
化疗耐药是急性髓系白血病（AML）患者治疗中的主要障碍。大多数AML患者在初次诊断时，即在接受化疗之前就对化疗存在内在耐药性；这种内在耐药性通常源于多药耐药基因（MDR - 1）的表达，该基因编码一种膜转运蛋白P - 糖蛋白（P - gp），它介导白血病细胞中的药物外排。在复发的白血病患者中，赋予多种形式多药耐药（MDR）的新型转运蛋白表达更为常见，如肺耐药蛋白（LRP）和多药耐药相关蛋白（MRP）。初步研究表明，这些蛋白也可能导致白血病的治疗耐药。在55岁以上的患者中，AML的特征是不良细胞遗传学、P - gp表达和功能性药物外排的频率较高，这导致了较差的临床结局。在多变量分析中，继发性AML、不良细胞遗传学以及P - gp表达/功能各自均与较低的完全缓解（CR）率显著且独立相关。耐药疾病与P - gp表达和不良细胞遗传学相关。令人惊讶的是，具有P - gp - 新发AML且细胞遗传学良好或中等的老年患者CR率为81%。具有不良细胞遗传学的P - gp + 继发性AML患者的CR率仅为12%。因此，在诊断时使用生物学参数对老年AML患者进行特征描述，可能有助于识别那些使用传统方案可能实现CR的患者，以及那些需要旨在克服MDR的替代治疗的患者。相比之下，在年龄小于50岁的AML患者中，仅25%至30%的患者检测到P - gp表达和功能性药物外排。虽然与老年AML患者相比，P - gp表达与年轻AML患者不良结局的相关性较弱，但它仍然与耐药疾病密切相关。正在进行研究以确定LRP和MRP在各种形式白血病中的预后意义。
