Richards Nigel G J, Kilberg Michael S
Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA.
Annu Rev Biochem. 2006;75:629-54. doi: 10.1146/annurev.biochem.75.103004.142520.
Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzyme-based methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.
现代儿童急性淋巴细胞白血病（ALL）临床治疗采用基于酶的方法消耗血液中的天冬酰胺，并结合标准化疗药物。这些治疗方案可能会产生显著的副作用，而且在许多情况下，患者会出现疾病的耐药形式，这可能与谷氨酰胺依赖性天冬酰胺合成酶（ASNS）的上调有关。尽管导致耐药性出现的确切分子机制是当前积极研究的课题，但强效ASNS抑制剂可能在治疗儿童ALL的天冬酰胺酶耐药形式方面具有临床应用价值。本综述概述了我们在以下两方面理解的最新进展：（a）ASNS的结构和催化机制，以及（b）ASNS在儿童ALL耐药性发生中可能发挥的作用。此外，还讨论了首次成功基于机制制备和表征纳摩尔级ASNS抑制剂的研究工作，以及这些研究对未来开发有效药物的意义。
