Reversal of MDR by verapamil analogues.
Reversal of MDR by verapamil analogues.
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DOI：
10.1080/10245330310001639009
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发表时间：
2004-02-01
期刊：
影响因子：
--
通讯作者：
Biscardi, Monica
中科院分区：
文献类型：
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作者：
Grossi, Alberto;Biscardi, Monica
多药耐药性 (MDR) 会导致多种血液恶性肿瘤的治疗失败，包括急性髓系白血病 (AML)、多发性骨髓瘤 (MM) 和非霍奇金淋巴瘤 (NHL)。这与蒽环类药物（多柔比星、柔红霉素、表柔比星）、长春花生物碱（长春新碱、长春花碱）、表鬼臼脂素（依托泊苷、替尼泊苷）、紫杉烷类（紫杉醇、多西紫杉醇）、拓扑替康和安吖啶尤其相关。细胞的 MDR 表型导致多效耐药性，从而导致难治性疾病的发展。 MDR 的经典机制包括药物外排泵、谷胱甘肽转移酶上调、拓扑异构酶 II 相关的 MDR 以及最近观察到的细胞外基质介导的 MDR [1]。主要而言，MDR 与 P-糖蛋白（Pgp 或 MDR1）的过度表达有关，P-糖蛋白是一种完整的膜蛋白，属于 ATP 结合盒 (ABC) 转运蛋白超家族，由位于 7 号染色体上的 mdr1 基因编码，作用于多种疏水性和两亲性大分子底物 [2]。 Pgp 的底物是罗丹明 123 和钙黄绿素-乙酰氧基甲酯 (calcein-AM) 等化合物，通常与单克隆抗体一起用于功能和表达分析。这种 170kDa 蛋白质的过度表达通常在接触细胞毒性药物后出现，与多种化合物的交叉耐药性相关，从而导致耐药性疾病。
Multidrug resistance (MDR) contributes to treatment failure in several hematologic malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL). This is particularly relevant with the anthracyclines (doxorubicin, daunorubicin, epirubicin), vinca alkaloids (vincristine, vinblastine), epipodophyllins (etoposide, teniposide), taxanes (paclitaxel, docetaxel), topotecan and amsacrine. The MDR phenotype of cells results in a pleiotropic drug resistance that leads to development of refractory disease. Classic mechanisms of MDR include drug efflux pumps, glutathione-transferase upregulation, topoisomerase II-associated MDR and, as recently observed, extracellular matrix-mediated MDR [1]. Principally, MDR is associated with overexpression of P-glycoprotein (Pgp or MDR1), an integral membrane protein, that belongs to a superfamily of ATP-binding cassette (ABC) transporters, encoded by the mdr1 gene located on chromosome 7 and acting on a wide range of substrates that are large hydrophobic and amphipatic molecules [2]. Substrates of Pgp are compounds such as rhodamine 123 and calcein-acetoxymethyl ester (calcein-AM) commonly used with monoclonal antibodies, for functional and expression analysis. Overexpression of this 170kDa protein, often developed after exposure to cytotoxic agents, is associated with cross-resistance to a wide range of compounds and consequently with a resistant disease.