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Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus.
- Source :
- JNCI: Journal of the National Cancer Institute; 12/01/99, Vol. 91 Issue 23, p2001-2008, 8p, 1 Diagram, 2 Charts, 5 Graphs
- Publication Year :
- 1999
-
Abstract
- <bold>Background: </bold>Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes.<bold>Methods: </bold>We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided.<bold>Results: </bold>Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations.<bold>Conclusion: </bold>We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait. [ABSTRACT FROM AUTHOR]
- Subjects :
- METHYLTRANSFERASES
PHENOTYPES
LYMPHOBLASTIC leukemia
Subjects
Details
- Language :
- English
- ISSN :
- 00278874
- Volume :
- 91
- Issue :
- 23
- Database :
- Complementary Index
- Journal :
- JNCI: Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 2594398
- Full Text :
- https://doi.org/10.1093/jnci/91.23.2001