DRUG-RESISTANCE IN MULTIPLE-MYELOMA AND NON-HODGKINS LYMPHOMA - DETECTION OF P-GLYCOPROTEIN AND POTENTIAL CIRCUMVENTION BY ADDITION OF VERAPAMIL TO CHEMOTHERAPY
DRUG-RESISTANCE IN MULTIPLE-MYELOMA AND NON-HODGKINS LYMPHOMA - DETECTION OF P-GLYCOPROTEIN AND POTENTIAL CIRCUMVENTION BY ADDITION OF VERAPAMIL TO CHEMOTHERAPY
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DOI：
10.1200/jco.1989.7.4.415
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发表时间：
1989-04-01
影响因子：
45.3
通讯作者：
SALMON, SE
中科院分区：
文献类型：
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作者：
DALTON, WS;GROGAN, TM;SALMON, SE
B细胞肿瘤，多发性骨髓瘤和非霍奇金淋巴瘤，经常成为耐药，尽管最初的反应化疗药物。通过免疫组化染色对8例临床药物难治性疾病患者的肿瘤细胞进行单克隆免疫球蛋白（Ig）表达、核增殖抗原、P-糖蛋白（P-gly）表达和其他细胞抗原的评价。在8名耐药疾病患者中，有6名患者的肿瘤细胞中检测到了P-gly。在6名P-gly阳性肿瘤患者中，5名患者患有晚期多发性骨髓瘤，1名患有药物难治性非霍奇金淋巴瘤。细胞RNA分析证实了P-gly的过表达。为了克服耐药性，一项初步研究评估了维拉帕米对这8例患者化疗的可能增强作用。所有患者在接受含长春新碱和多柔比星的治疗方案时均发生疾病进展，8例患者中有7例既往接受过长春新碱和多柔比星持续输注加口服地塞米松（VAD）。在疾病进展时，在VAD方案中加入持续输注维拉帕米。当维拉帕米加用VAD时，8例对长春新碱和多柔比星单药治疗无效的患者中有3例有反应。有反应的三名患者患有P-gly阳性肿瘤。维拉帕米在体外增加了P-gly阳性骨髓瘤细胞系和两名过表达P-gly的终末期骨髓瘤患者的肿瘤细胞中多柔比星和长春新碱的细胞内蓄积。在化疗中加入维拉帕米的剂量限制性副作用是暂时性心功能损害，表现为低血压和心律失常。我们的结论是，P-gly表达发生在药物难治性B细胞肿瘤，并可能有助于临床耐药的发展。然而，其他因素，如肿瘤的增殖活性，也可能在决定对化疗的反应中发挥作用。维拉帕米沿着VAD化疗可部分避免肿瘤过度表达P-gly患者的耐药性。
The B-cell neoplasms, multiple myeloma and non-Hodgkin''s lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immunohistochemical staining for monoclonal immunoglobulin (lg) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug refractory non-Hodgkin''s lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAd regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAd chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.