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Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers in PURINERGIC SIGNALLING, vol 6, issue , pp 33-33
Newcastle University, UK.
Newcastle University, UK.
Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.ORCID-id: 0000-0002-2809-7591
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2010 (engelsk)Inngår i: PURINERGIC SIGNALLING, Springer Science Business Media , 2010, Vol. 6, s. 33-33Konferansepaper, Publicerat paper (Fagfellevurdert)
Abstract [en]

The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used in the treatment of leukaemia. 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. Since the growth of MTAP-deleted tumour 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 leukaemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP-ve) transfected to express MTAP constitutively (A549-MTAP+ve). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intra-cellularly to MeTIMP, was markedly higher in both cell lines under MTAP-ve 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.

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Springer Science Business Media , 2010. Vol. 6, s. 33-33
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Identifikatorer
URN: urn:nbn:se:liu:diva-60501ISI: 000280241700070OAI: oai:DiVA.org:liu-60501DiVA, id: diva2:357059
Tilgjengelig fra: 2010-10-15 Laget: 2010-10-15 Sist oppdatert: 2013-09-03bibliografisk kontrollert

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