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Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers

Lookup NU author(s): Dr Sally Coulthard, Dr Chris Redfern, Svante Vikingsson, Dr Malin Lindqvist Appell, Emeritus Professor Andy Hall, Gordon Taylor, Dr Linda Hogarth

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Abstract

The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP. Mol Cancer Ther; 10(3); 495-504. (C)2011 AACR


Publication metadata

Author(s): Coulthard SA, Redfern CPF, Vikingsson S, Lindqvist-Appell M, Skoglund K, Jakobsen-Falk I, Hall AG, Taylor GA, Hogarth LA

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Therapeutics

Year: 2011

Volume: 10

Issue: 3

Pages: 495-504

Print publication date: 31/01/2011

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1535-7163.MCT-10-0798

DOI: 10.1158/1535-7163.MCT-10-0798


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