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The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs

Lookup NU author(s): Dr Sally Coulthard, Dr Linda Hogarth, Dr Margaret Little, Elizabeth Matheson, Dr Chris Redfern, Lynne Minto, Emeritus Professor Andy Hall

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Abstract

Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleotides into newly synthesized DNA (DNA-TGN), an important component of the mode of action of 6-MP is inhibition of purine de novo synthesis (PDNS) through the production of S-methyl-thioinosine 5′-monophosphate (MeTIMP), not formed in cells exposed to 6-TG. We have shown that thiopurine methyltransferase (TPMT) modulates this effect. By transfection of the human TPMT gene using an inducible system to produce a 3.8-fold increase in TPMT activity in the ecdysone receptor 293 embryonic kidney cell line, we demonstrated a 4.4-fold increase in sensitivity to 6-MP. This was associated with a rise in intracellular levels of MeTIMP but a decrease in levels of DNA-TGN. In contrast, induction of TPMT produced a 1.6-fold decrease in sensitivity to 6-TG, a decrease in levels of DNA-TGN, and an increase in levels of methylated thioguanosine monophosphate. Exposure of cells to equitoxic doses of drug showed similar incorporation of DNA-TGN for 6-TG but for 6-MP significantly reduced DNA-TGN in TPMT-induced compared with uninduced cells. For equitoxic doses of 6-MP, equivalent levels of MeTIMP correlated with equivalent amounts of PDNS. These observations suggest that intracellular TGN levels do not give an accurate reflection of cytotoxic potential in patients treated with 6-MP, because different levels of DNA-TGN may be associated with equitoxic effects.


Publication metadata

Author(s): Coulthard, S.A., Hogarth, L.A., Little, M.A., Matheson, E., Redfern, C.P.F., Minto, C.L.J., Hall, A.G.

Publication type: Article

Publication status: Published

Journal: Molecular Pharmacology

Year: 2002

Volume: 62

Issue: 1

Pages: 102-109

Print publication date: 01/01/2002

ISSN (print): 0026-895X

ISSN (electronic): 1521-0111

URL: http://dx.doi.org/10.1124/mol.62.1.102

DOI: 10.1124/mol.62.1.102

PubMed id: 12065760


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