Wilson W H, Bates S E, Fojo A, Bryant G, Zhan Z, Regis J, Wittes R E, Jaffe E S, Steinberg S M, Herdt J
Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA.
J Clin Oncol. 1995 Aug;13(8):1995-2004. doi: 10.1200/JCO.1995.13.8.1995.
Overexpression of the multidrug resistance gene (mdr-1) is present in up to 60% of relapsed lymphomas. To study its role in lymphomas, we conducted a controlled trial of dexverapamil, an inhibitor of the mdr-1 gene product, P-glycoprotein (Pgp), in lymphomas refractory to etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy.
Eligible patients had recurrent Hodgkin's (HD) or non-Hodgkin's lymphomas (NHL) and measurable disease. Patients initially received EPOCH alone and those with stable tumor over two cycles or progressive disease crossed over to receive dexverapamil and EPOCH on subsequent cycles. Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR).
Of 154 patients entered onto the trial, 109 had NHL and 45 had HD. The median age was 44 years, 67% had stage IV disease, and the median number of prior regimens was two (range, one to 12) in NHL and one (range, one to four) in HD. Sixty-four patients (42%) crossed over, of which eight were not assessable. The maximum-tolerated dose of dexverapamil was 900 mg/m2/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs. The mdr-1 level was measured in 44 biopsies from 19 patients. Pretherapy, mdr-1 was low (median, 2.5 U) but increased (median, 12.2 U) at crossover. Of six patients with mdr-1 levels greater than 15 U, three responded to dexverapamil, while only one of eight patients with mdr-1 levels less than 15 U responded. EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity.
These results suggest that Pgp plays a role in clinical drug resistance of lymphomas. However, they also suggest that mechanisms other than Pgp are prominent in heavily pretreated patients and that, although Pgp inhibition may be necessary, it is probably insufficient. Earlier intervention with dexverapamil may be more effective and warrants further study.
多药耐药基因（mdr - 1）在高达60%的复发性淋巴瘤中呈过表达。为研究其在淋巴瘤中的作用，我们开展了一项关于右维拉帕米的对照试验，右维拉帕米是mdr - 1基因产物P - 糖蛋白（Pgp）的抑制剂，用于治疗对依托泊苷、泼尼松、长春新碱、环磷酰胺和阿霉素（EPOCH）化疗耐药的淋巴瘤。
符合条件的患者患有复发性霍奇金淋巴瘤（HD）或非霍奇金淋巴瘤（NHL）且有可测量的病灶。患者最初仅接受EPOCH治疗，那些经过两个周期肿瘤稳定或病情进展的患者在后续周期交叉接受右维拉帕米和EPOCH治疗。右维拉帕米分八个剂量水平递增，从240至1200 mg/m²/天。尽可能获取系列活检样本，通过定量聚合酶链反应（PCR）检测mdr - 1表达。
154例患者进入试验，其中109例为NHL，45例为HD。中位年龄为44岁，67%患者为IV期疾病，NHL患者既往治疗方案的中位数为2种（范围1至12种），HD患者为1种（范围1至4种）。64例患者（42%）进行了交叉治疗，其中8例无法评估。右维拉帕米的最大耐受剂量为900 mg/m²/天。在41例NHL患者（不包括蕈样霉菌病）中，有3例完全缓解（CR），2例部分缓解（PR）（12%），5例轻微缓解（MR）；10例HD患者中有2例达到PR。对19例患者的44份活检样本检测了mdr - 1水平。治疗前，mdr - 1水平较低（中位数为2.5 U），但在交叉治疗时升高（中位数为12.2 U）。在mdr - 1水平大于15 U的6例患者中，3例对右维拉帕米有反应，而mdr - 1水平小于15 U的8例患者中只有1例有反应。EPOCH和右维拉帕米耐受性良好，但与单独使用EPOCH相比，产生了更多的血液学毒性。
这些结果表明Pgp在淋巴瘤的临床耐药中起作用。然而，它们也表明在经过大量预处理的患者中，除Pgp外的其他机制也很突出，并且尽管抑制Pgp可能是必要的，但可能并不充分。早期使用右维拉帕米干预可能更有效，值得进一步研究。
