Drug resistance: still a daunting challenge to the successful treatment of AML.
Drug resistance: still a daunting challenge to the successful treatment of AML.
复制标题
DOI：
10.1016/j.drup.2012.02.001
复制
发表时间：
2012-02
影响因子：
24.3
通讯作者：
Gottesman, Michael M.
中科院分区：
文献类型：
--
作者：
Shaffer, Brian C.;Gillet, Jean-Pierre;Patel, Chirayu;Baer, Maria R.;Bates, Susan E.;Gottesman, Michael M.
对病人和他们的医生来说，化疗耐药性仍然是一个具有挑战性的问题。p -糖蛋白（Pgp, MDR1, ABCB1），以及一系列结构和功能相关的蛋白，是能够从细胞质外排各种底物的质膜转运蛋白，包括化疗药物。ABCB1的发现为药理学下调外排介导的化疗耐药提供了一个潜在的靶点。急性髓系白血病（AML）是一种以低分化髓系祖细胞增殖为特征的肿瘤，白血病细胞通常高水平表达ABCB1，这可能导致对化疗产生耐药性。因此，AML似乎是一种可能的癌症，在化疗方案中加入药物外排抑制剂将改善患者的预后。尽管有这个合理的假设，但大多数评估这一策略的临床试验都未能达到积极的终点，最近的是东方肿瘤合作组织的E3999试验。在这里，我们回顾了表明ABCB1在AML中的重要性的数据，解决了临床试验的失败，以支持旨在调节ABCB1介导的耐药的治疗策略，并考虑了该领域未来应该进行的研究类型。
Resistance to chemotherapy remains a challenging issue for patients and their physicians. P-glycoprotein (Pgp, MDR1, ABCB1), as well as a family of structurally and functionally related proteins, are plasma membrane transporters able to efflux a variety of substrates from the cell cytoplasm, including chemotherapeutic agents. The discovery of ABCB1 made available a potential target for pharmacologic down-regulation of efflux-mediated chemotherapy resistance. In patients with acute myeloid leukemia (AML), a neoplasm characterized by proliferation of poorly differentiated myeloid progenitor cells, leukemic cells often express ABCB1 at high levels, which may lead to the development of resistance to chemotherapy. Thus, AML seemed to be a likely cancer for which the addition of drug efflux inhibitors to the chemotherapeutic regimen would improve outcomes in patients. Despite this rational hypothesis, the majority of clinical trials evaluating this strategy have failed to reach a positive endpoint, most recently the Eastern Cooperative Oncology Group E3999 trial. Here we review data suggesting the importance of ABCB1 in AML, address the failure of clinical trials to support a therapeutic strategy aimed at modulating ABCB1-mediated resistance, and consider the type of research that should be conducted in this field going forward.
登录
查看更多内容
DOI：
10.1016/j.bbapap.2009.02.014
发表时间：
2009-05
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Fung KL;Gottesman MM
通讯作者：
Gottesman MM
影响因子：
4.8
作者：
Bram, Eran E.;Stark, Michal;Assaraf, Yehuda G.
通讯作者：
Assaraf, Yehuda G.
影响因子：
64.5
作者：
Gupta PB;Onder TT;Jiang G;Tao K;Kuperwasser C;Weinberg RA;Lander ES
通讯作者：
Lander ES
影响因子：
20.3
作者：
Abbott, BL;Colapietro, AM;Sorrentino, BP
通讯作者：
Sorrentino, BP
影响因子：
4.3
作者：
Bacher, Ulrike;Haferlach, Torsten;Haferlach, Claudia
通讯作者：
Haferlach, Claudia