title: Expression of asparagine synthetase predicts in vitro response to L-asparaginase in canine lymphoid cell lines.
abstract: l-asparaginase (L-asp), a bacterial enzyme that depletes extracellular asparagine, is used to treat acute lymphoblastic leukemia in humans and a variety of aggressive lymphoid malignancies in dogs. Resistance to this drug is an important cause of treatment failure in both species. Using canine lymphoid cell lines, we found that L-asp sensitivity is strongly negatively correlated with the level of methylation of the asparagine synthetase (ASNS) promoter. Selection for in vitro resistance was accompanied by increased ASNS promoter methylation and decreased ASNS mRNA expression. In addition, treatment with the hypomethylating agent 5-azacytidine increased resistance to L-asp. ASNS methylation and expression is not predictive of overall survival or progression-free survival in canine lymphoma patients treated with L-asp. Our data suggest that ASNS is an important factor in mediating the in vitro response of canine lymphoid cells to L-asp; however, resistance mechanisms may be more complex in dogs treated clinically with L-asp, potentially due to concurrent treatments.
authors.affiliation: University of North Carolina at Chapel Hill, NC , USA.
authors.forename: Tangi L
authors.initials: TL
authors.lastname: Smallwood
authors.forename: George W
authors.initials: GW
authors.lastname: Small
authors.forename: Steven E
authors.initials: SE
authors.lastname: Suter
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Richards
mesh_terms: D000818:Animals; D001215:Asparaginase / Q000008:administration & dosage / Q000494:pharmacology*; D001217:Aspartate-Ammonia Ligase / Q000235:genetics* / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004195:Disease Models, Animal; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase; D001374:Azacitidine
keywords: Asparagine synthetase; comparative oncology; l-asparaginase; lymphoma; methylation