Salmon S E, Dalton W S, Grogan T M, Plezia P, Lehnert M, Roe D J, Miller T P
Arizona Cancer Center, Tucson 85724.
Blood. 1991 Jul 1;78(1):44-50.
Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1), doxorubicin (Adriamycin) and vincristine sensitivity, and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro, but did not enhance sensitivity of cells that were drug sensitive (P less than .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials, 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve, five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive, four responded clinically (40%), whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil, whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development, in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies, including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.
维拉帕米作为一种化学增敏剂，在体外实验和临床试验中均被用于评估其逆转多发性骨髓瘤多药耐药性的效果。对59例复发的骨髓瘤患者的骨髓进行了多项耐药参数评估：P-糖蛋白（MDR1）的表达、阿霉素（多柔比星）和长春新碱的敏感性，以及添加维拉帕米后降低对细胞毒性药物耐药性的能力。我们发现，维拉帕米能够使体外对阿霉素和长春新碱耐药的骨髓瘤细胞敏感，但对药物敏感的细胞没有增强其敏感性（P小于0.001）。免疫组化显示表达MDR1的骨髓瘤细胞在体外往往比MDR1阴性细胞对阿霉素更耐药。在临床试验中，22例对长春新碱-阿霉素-地塞米松（VAD）耐药的骨髓瘤患者接受了VAD加静脉高剂量维拉帕米（Ve）治疗。在接受VAD/Ve治疗的22例患者中，5例获得部分缓解（23%）。VAD/Ve治疗有反应者的无复发生存期中位数为5.4个月，从开始VAD/Ve治疗起他们的总生存期优于无反应者。在骨髓瘤细胞MDR1阳性的10例患者亚组中，4例有临床反应（40%），而5例MDR1阴性骨髓瘤细胞患者中无1例通过VAD/Ve获得缓解。我们还观察到，4例VAD/Ve临床有反应者中有3例的骨髓瘤细胞在体外对维拉帕米有化学增敏作用，而6例临床无反应者中只有1例在体外有维拉帕米化学增敏作用。我们的观察结果表明，使用维拉帕米可使一些对VAD耐药的骨髓瘤患者实现多药耐药的临床逆转。除了在药物研发中的价值外，对患者骨髓骨髓瘤细胞进行MDR1表达以及化学增敏剂加细胞毒性药物的体外试验，可能有助于识别对含化学增敏剂方案有临床反应的患者。我们预计，能够抑制多药耐药的化学增敏剂方案在血液系统恶性肿瘤的治疗中将发挥越来越重要的作用，包括B细胞肿瘤，如多发性骨髓瘤和非霍奇金淋巴瘤。
