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: Sally A Coulthard, Christopher P F Redfern, Svante Vikingsson, Malin Lindqvist-Appell, Karin Skoglund, Ingrid Jakobsen-Falk, Andrew G Hall, Gordon A Taylor, Linda A Hogarth
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 3 Pg. 495-504 (Mar 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21282358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Antimetabolites, Antineoplastic
• Purines
• Thionucleotides
• Thioinosine
• 6-methylthiopurine ribonucleoside-5'-phosphate
• Mercaptopurine
• Purine-Nucleoside Phosphorylase
• 5'-methylthioadenosine phosphorylase
• Thioguanine
• purine

Topics

• Antimetabolites, Antineoplastic (metabolism, pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Deletion
• Humans
• Immunoblotting
• Mercaptopurine (metabolism, pharmacology, therapeutic use)
• Neoplasms (drug therapy, genetics, metabolism)
• Purine-Nucleoside Phosphorylase (deficiency, genetics, metabolism)
• Purines (biosynthesis)
• Thioguanine (metabolism, pharmacology, therapeutic use)
• Thioinosine (analogs & derivatives, pharmacology)
• Thionucleotides (pharmacology)