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Coulthard, Sally A.; Redfern, Christopher P.F.; Vikingsson, Svante; Lindqvist-Appell, Malin; Skoglund, Karin; Jakobsen-Falk, Ingrid; Hall, Andrew G.; Taylor, Gordon A.; Hogarth, Linda A.

Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase–Deleted Cancers

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  • Media type: E-Article
  • Title: Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase–Deleted Cancers
  • Contributor: Coulthard, Sally A.; Redfern, Christopher P.F.; Vikingsson, Svante; Lindqvist-Appell, Malin; Skoglund, Karin; Jakobsen-Falk, Ingrid; Hall, Andrew G.; Taylor, Gordon A.; Hogarth, Linda A.
  • imprint: American Association for Cancer Research (AACR), 2011
  • Published in: Molecular Cancer Therapeutics
  • Language: English
  • DOI: 10.1158/1535-7163.mct-10-0798
  • ISSN: 1538-8514; 1535-7163
  • Keywords: Cancer Research ; Oncology
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dGs) 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 dGs 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. ©2011 AACR.</jats:p>
  • Access State: Open Access