Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies
Acute promyelocytic leukemia: recent advances in therapy and molecular basis of response to arsenic therapies
复制标题
DOI：
10.1097/01.moh.0000148552.93303.45
复制
发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Dang, CV
中科院分区：
文献类型：
--
作者：
Chou, WC;Dang, CV
综述目的虽然砷长期以来被认为是一种有毒的环境致癌物，但它在治疗急性早幼粒细胞白血病(APL)中的显著作用使其作用机制成为人们密切关注的话题。本文回顾了最近的研究结果，揭示了为什么一种传统的毒药已经成为治疗一种主要类型的APL的神奇药剂，这种类型的APL的特点是染色体平衡易位t(15；17)。最近的研究发现，每天静脉注射三氧化二砷(As2O3；ATO)30-40天可以导致大约85%的初诊或复发APL患者完全缓解。口服ATO和四硫化四砷(As4S4)似乎与静脉注射ATO一样有效，毒性特征相似。在新诊断的APL患者中，全反式维甲酸和ATO的联合治疗比单一治疗产生了更持久的缓解。砷的细胞毒性机制被认为涉及翻译后修饰，随后降解PML-维甲酸受体-α(PML-RARpha)融合蛋白；将PML靶向核体，恢复其生理功能；通过NADPH氧化酶在白血病细胞中产生活性氧(ROS)或使线粒体跨膜电位崩溃。对砷细胞毒性的认识促进了有望提高疗效的修饰，如干扰ROS的清除或促进ROS的产生以增强细胞毒性，以及在ATO方案中加入cAMP或干扰素。综述了近年来砷的临床应用，砷介导的细胞毒性的机制，以及ATO的调节以提高其疗效和扩大其临床谱。
Purpose of reviewWhile arsenic has long been known as a poison and environmental carcinogen, its dramatic effect in the treatment of acute promyelocytic leukemia (APL) has made its mechanism of action a topic of intense interest. This paper reviews recent findings that reveal why a traditional poison has become a magical potion for a major type of APL, which is characterized by a balanced chromosomal translocation t(15;17).Recent findingsDaily IV fusion of arsenic trioxide (As2O3;ATO) for 30 to 40 days can lead to complete remission in about 85% of patients with newly diagnosed or relapsed APL. Oral preparations of ATO and tetra-arsenic tetra-sulfide (As4S4) seem to be as effective as parenteral ATO, with similar toxicity profiles. The combination of all-trans retinoic acid and ATO in patients with newly diagnosed APL has yielded more durable remission than monotherapy. The mechanism of arsenic cytotoxicity is thought to involve posttranslational modification followed by degradation of the PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein; targeting of PML to nuclear bodies with restoration of its physiologic functions; and production of reactive oxygen species (ROS) by NADPH oxidase in leukemic cells or collapse of the mitochondrial transmembrane potential. The understanding of arsenic cytotoxicity has stimulated modifications that promise to improve efficacy, such as interfering with ROS scavenging or boosting of ROS production to enhance the cytotoxicity, and adding cAMP or interferons to ATO regimens.SummaryRecent advances in the clinical use of arsenic, the mechanism of arsenic-mediated cytotoxicity, and modulations of ATO to increase its efficacy and expand its clinical spectrum are reviewed.