Ozpolat B, Lopez-Berestein G, Mehta K
Department of Bioimmunotherapy, The University of Texas, MD Anderson Cancer Center, Houston 77030, USA.
J Biol Regul Homeost Agents. 2001 Apr-Jun;15(2):107-22.
Acute promyelocytic leukemia (APL) is a unique disease that responds to differentiation-inducing effects of all-trans-retinoic acid (ATRA). ATRA induces complete clinical remissions (CRs) in most patients and now constitutes a standard therapy in patients with APL. However, CRs induced by ATRA are usually brief, and resistance to the therapy rapidly develops, leading to relapses in almost every patient; thus limiting the use of ATRA as a single agent. On the basis of clinical and in vitro studies, the following mechanisms have been proposed to explain ATRA resistance: 1) induction of accelerated metabolism of ATRA, 2) increased expression of cellular retinoic acid-binding proteins (CRABPs), 3) constitutive degradation of PML-RAR alpha, 4) point mutations in the ligand-binding domain of RAR alpha of PML-RAR alpha, 5) P-glycoprotein expression, 6) transcriptional repression by histone deacetylase activity, 7) isoforms of PML-RAR alpha, 8) persistent telomerase activity, and 9) expression of type II transglutaminase. In this review, we discuss the evidence provided in support of each mechanism, the mechanism's possible impact on the outcome of APL, and the newer approaches that are being employed to overcome ATRA resistance.
急性早幼粒细胞白血病（APL）是一种独特的疾病，对全反式维甲酸（ATRA）的诱导分化作用有反应。ATRA能使大多数患者实现完全临床缓解（CR），目前已成为APL患者的标准治疗方法。然而，ATRA诱导的CR通常很短暂，且对该疗法的耐药性迅速产生，几乎导致每个患者复发；因此限制了ATRA作为单一药物的使用。基于临床和体外研究，已提出以下机制来解释ATRA耐药性：1）诱导ATRA加速代谢，2）细胞视黄酸结合蛋白（CRABP）表达增加，3）PML-RARα的组成性降解，4）PML-RARα的RARα配体结合域中的点突变，5）P-糖蛋白表达，6）组蛋白脱乙酰酶活性导致的转录抑制，7）PML-RARα的异构体，8）持续的端粒酶活性，以及9）II型转谷氨酰胺酶的表达。在本综述中，我们讨论了支持每种机制的证据、该机制对APL预后可能产生的影响，以及为克服ATRA耐药性而采用的新方法。
