title: Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers.
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.
authors.affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom. S.A.Coulthard@newcastle.ac.uk
authors.forename: Sally A
authors.initials: SA
authors.lastname: Coulthard
authors.forename: Christopher P F
authors.initials: CP
authors.lastname: Redfern
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.forename: Malin
authors.initials: M
authors.lastname: Lindqvist-Appell
authors.forename: Karin
authors.initials: K
authors.lastname: Skoglund
authors.forename: Ingrid
authors.initials: I
authors.lastname: Jakobsen-Falk
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Hall
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Linda A
authors.initials: LA
authors.lastname: Hogarth
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D017353:Gene Deletion; D006801:Humans; D015151:Immunoblotting; D015122:Mercaptopurine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000096:biosynthesis; D013866:Thioguanine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D011687:Purines; D013873:Thionucleotides; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D013866:Thioguanine; C030985:purine