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Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers
Newcastle University.
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-2809-7591
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
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2011 (English)In: MOLECULAR CANCER THERAPEUTICS, ISSN 1535-7163, Vol. 10, no 3, 495-504 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA , 2011. Vol. 10, no 3, 495-504 p.
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Medical and Health Sciences
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URN: urn:nbn:se:liu:diva-67042DOI: 10.1158/1535-7163.MCT-10-0798ISI: 000288153900012OAI: oai:DiVA.org:liu-67042DiVA: diva2:406300
Available from: 2011-03-25 Created: 2011-03-25 Last updated: 2014-01-09Bibliographically approved

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Lindqvist Appell, MalinSkoglund, KarinJakobsen Falk, Ingrid

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