Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics.

Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Research Abstract Details 

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Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Abstract Text:

Christine Hartford,Erick Vasquez,Matthias Schwab,Mathew J Edick,Jerold E Rehg,Gerard Grosveld,Ching-Hon Pui,William E Evans,Mary V Relling,

The recessive deficiency in thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT, can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of thiopurines is not known. To address these issues, we created a murine knockout of Tpmt. Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) mice and variables were compared among genotypes. Methylated thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine (P < 0.0001 and P = 0.044, respectively) and thioguanine (P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt(-/-), Tpmt(+/-), and Tpmt(+/+) genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy.

Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Publishing Authors By Initials

C Hartford,E Vasquez,M Schwab,MJ Edick,JE Rehg,G Grosveld,CH Pui,WE Evans,MV Relling,

For similar heterocyclic compounds: heterocyclic compounds, 2-ring: purines: thioguanine research abstracts see: heterocyclic compounds: heterocyclic compounds, 2-ring: purines: thioguanine research

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Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 67

Page Numbers: 4965-72

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 15

MONTH: May

YEAR: 2007

Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Keywords Mesh Terms:

KEYWORDS: Thioguanine

MESH TERMS: toxicity

Chemical & Substance for Abstract: Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics. Information

Substance Name: thiopurine methyltransferase

Registry Number: EC 2.1.1.67

Grant and Affiliation Information for Differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics.

AFFILIATION: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, University of Tennessee, Memphis, Tennessee, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: U01 GM61393

ACRONYM: GM

MEDLINETA: Cancer Res

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