Sonneveld P, Lokhorst H M, Vossebeld P
Department of Hematology, University Hospital Rotterdam, Dijkzigt, The Netherlands.
Semin Hematol. 1997 Oct;34(4 Suppl 5):34-9.
The development of multidrug resistance (MDR) is a major obstacle to improving treatment outcomes in multiple myeloma. Recent studies have indicated that several specific mechanisms of MDR may be involved in clinically refractory multiple myeloma patients, such as expression of P-glycoprotein (P-gp), expression of the lung-resistance protein (LRP) and suppression of apoptosis via expression of Bcl-2. The emergence of these mechanisms of MDR in multiple myeloma is enhanced by exposure to chemotherapeutic agents. Recently, clinical reversal of MDR by noncytotoxic P-gp modulators such as verapamil, cyclosporin A (CsA), and PSC 833 was explored in acute leukemia and multiple myeloma. Preliminary results from clinical phase I/II trials indicate that reversal of MDR via modulation of P-gp is possible and that coadministration of these MDR modulators with chemotherapeutic agents alters the plasma pharmacokinetics of chemotherapeutic agents. Phase II and III clinical trials investigating the efficacy of these and other agents in the reversal of MDR in hematologic malignancies are ongoing.
多药耐药（MDR）的发展是改善多发性骨髓瘤治疗效果的主要障碍。最近的研究表明，MDR的几种特定机制可能与临床难治性多发性骨髓瘤患者有关，如P-糖蛋白（P-gp）的表达、肺耐药蛋白（LRP）的表达以及通过Bcl-2表达抑制细胞凋亡。接触化疗药物会增强多发性骨髓瘤中这些MDR机制的出现。最近，在急性白血病和多发性骨髓瘤中探索了使用维拉帕米、环孢素A（CsA）和PSC 833等非细胞毒性P-gp调节剂对MDR进行临床逆转。I/II期临床试验的初步结果表明，通过调节P-gp逆转MDR是可能的，并且这些MDR调节剂与化疗药物联合使用会改变化疗药物的血浆药代动力学。正在进行II期和III期临床试验，以研究这些药物和其他药物在血液系统恶性肿瘤中逆转MDR的疗效。
