Asparagine synthetase chemotherapy.
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.
Richards
Nigel G J
NG
Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA. richards@qtp.ufl.edu
Kilberg
Michael S
MS
D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001216:Asparagine / Q000096:biosynthesis; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology; D011487:Protein Conformation; D013449:Sulfonamides / Q000737:chemistry; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D001216:Asparagine; D001217:Aspartate-Ammonia Ligase