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Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers
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- Coulthard, Sally A (author)
- Newcastle University
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- Redfern, Christopher P F (author)
- Linköpings universitet,Farmakologi,Hälsouniversitetet
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- Lindqvist Appell, Malin (author)
- Linköpings universitet,Klinisk farmakologi,Hälsouniversitetet
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- AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA, 2011
- 2011
- English.
- In: MOLECULAR CANCER THERAPEUTICS. - : AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA. - 1535-7163. ; 10:3, s. 495-504
- Journal article (peer-reviewed)
Abstract
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- 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.
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