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The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment

Lookup NU author(s): Dr Sally Coulthard, Emeritus Professor Andy Hall, Dr Linda Hogarth

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Abstract

Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood. Although current treatment results in long term survival in over 70% of cases there is evidence that as many as 50% could have been cured using a less complex regimen with a lower incidence of long term side effects. In previous studies it has been found that thiopurines given as part of continuing therapy are key agents in preventing relapse. However, optimal administration during continuing therapy is often not achieved. Variation in the level of thiopurine methyltransferase (TPMT) activity appears to be a major molecular determinant of the extent of thiopurine metabolism. TPMT activity shows a trimodal distribution pattern. A lack of activity is found in approximately one in 300 Caucasians; approximately 11% have intermediate activity and the remaining 89% high activity. Congenital loss of activity is associated with grossly elevated levels of active drug and profound myelosuppression on exposure to thiopurines. This loss of activity has been attributed to single nucleotide polymorphisms (SNPs) within the TPMT gene. The frequency of SNPs is related to ethnicity, with the most common in Caucasians being TPMT*3A which is characterized by a G to A transition at position 460 with a substitution of alanine for tyrosine at amino acid 154 (A154Y) and a transition of A to G at nucleotide 719 resulting in a change of tyrosine to cysteine at position 240 (Y240C). Polymorphisms have also been identified within the 5' flanking promoter region of the TPMT gene due to a variable number of tandem repeats (VNTR*3-*8). An overview of the polymorphisms identified to date, their implication on the metabolism of the thiopurine drugs and therapeutic importance will be discussed.


Publication metadata

Author(s): Coulthard SA, Matheson EC, Hall AG, Hogarth LA

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: Joint 11th International and 9th European Symposium on Purines and Pyrimidines

Year of Conference: 2004

Pages: 1385-1391

Publisher: Nucleosides, Nucleotides and Nucleic Acids: Taylor & Francis Inc.

URL: http://dx.doi.org/10.1081/NCN-200027637

DOI: 10.1081/NCN-200027637

PubMed id: 15571264

Library holdings: Search Newcastle University Library for this item

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