Abstract
Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMT-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.
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References
Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE . Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia Blood 1999 93: 2817–2823
McLeod HL, Coulthard S, Thomas AE, Pritchard SC, King DJ, Richards SM, Eden OB, Hall AG, Gibson BES . Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia Br J Haematol 1999 105: 696–700
Krynetski EY, Evans WE . Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm Pharmaceut Res 1999 16: 342–349
Krynetski EY, Tai HL, Yates CR, Fessing MY, Loennechen T, Schuetz JD, Relling MV Evans WE . Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms Pharmacogenetics 1996 6: 279–290
Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM . Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukemia Lancet 1990 336: 225–229
Evans WE, Horner M, Chu YO, Kalwinsky D, Roberts WM . Altered mercaptopurine metabolism, toxic effects and dosage requirement in a thiopurine methyltranferase-deficient child with acute lymphoblastic leukemia J Pediatr 1991 119: 985–989
McLeod HL, Miller DR, Evans WE . Azathioprine induced myelosuppression in thiopurine methyltransferase deficient heart-transplant recipient Lancet 1993 341: 1151
Schutz E, Gummert J, Mohr F, Oellerich M . Azathioprine induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient Lancet 1993 341: 436
McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE . Thiopurine methyltransferase activity in American white subjects and black subjects Clin Pharm Ther 1994 55: 15–20
Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, Relling MV, Evans WE . Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance Ann Intern Med 1997 126: 608–616
Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, ParkHah JO, Iven H, Schmiegelow K, Branum E, Obrain J, Weinshilboum R . Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms Clin Pharmacol Ther 1997 62: 60–73
Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, Evans WE . Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians Am J Hum Genet 1993 58: 694–702
Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE . Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity Proc Natl Acad Sci USA 1997 94: 6444–6449
delaMoureyre CSV, Debuysere H, Sabbagh N, Marez D, Vinner E, Chevalier ED, LoGuidice JM, Broly F . Detection of known and new mutations in the thiopurine S-methyltransferase gene bysingle-strand conformation polymorphism analysis Hum Mutat 1998 12: 177–185
Otterness DM, Szumlanski CL, Wood TC, Weinshilboum RM . Human thiopurine methyltransferase pharmacogenetics–kindred with a terminal exon splice junction mutation that results in loss of activity J Clin Invest 1998 101: 1036–1044
Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE . A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase Proc Natl Acad Sci USA 1995 92: 949–953
Tai HL, Fessing MY, Bonten EJ, Yanishevsky Y, d'Azzo A, Krynetski EY, Evans WE . Enhanced proteasomal degradation of mutant human thiopurine S-methyltransferase (TPMT) in mammalian cells: mechanism for TPMT protein deficiency inherited by TPMT*2, TPMT*3A, TPMT*3B or TPMT*3C Pharmacogenetics 1999 9: 641–650
Loennechen T, Yates CR, Fessing MY, Relling MV, Krynestski EY, Evans WE . Isolation of a human thiopurine S-methyltransferase (TPMT) complementary DNA with a single nucleotide transition A719G (TPMT*3C) and its association with loss of TPMT protein and catalytic activity in humans Clin Pharmacol Ther 1998 64: 46–51
Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE . Polymorphism of the thiopurine S-methyltransferase gene in African–Americans Hum Mol Gen 1999 8: 371–376
Ameyaw MM, Collie-Duguid ESR, Powrie RH, Ofori-Adjei D, McLeod HL . Thiopurine methyltransferase alleles in British and Ghanaian populations Hum Mol Gen 1999 8: 367–370
Collie-Duguid ESR, Prichard SC, Powrie RH, Sludden J, Collier DA, Li T, McLeod HL . The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations Pharmacogenetics 1999 9: 37–42
McLeod HL, Pritchard SC, Githang'a J, Indalo A, Ameyaw MM, Powrie RH, Booth L, Collie-Duguid ESR . Ethnic differences in thiopurine methyltransferase pharmacogenetics: evidence for allele specificity in Caucasian and Kenyan subjects Pharmacogenetics 1999 9: 773–776
Kumagai K, Hiyama K, Ishioka S, Sato H, Yamanishi Y, McLeod HL, Konishi F, Maeda H, Yamakido M . Allelotype frequency of the thiopurine methyltransferase gene in Japanese Pharmacogenetics (in press)
Coulthard SA, Howell C, Robson J, Hall AG . The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia Blood 1998 92: 2856–2862
delaMoureyre CSV, Debuysere H, Mastain B, Vinner E, Marez D, LoGuidice JM, Chevalier D, Brique S, Motte K, Colombel JF, Turck D, Noel C, Flipo EM, Pol A, Lhermitte M, Lafitte JJ, Libersa C, Broly F . Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population Br Pharmacol 1998 125: 879–887
Black AJ, McLeod HL, Capell HA, Powrie RH, Matowe LK, Pritchard SC, Collie-duguid ESR, Reid DM . Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine Ann Intern Med 1998 129: 716–718
McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE . Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic-leukemia Blood 1995 85: 1897–1902
Relling MV, Hancock HL, Rivera GK, Sandlund JT, Ribeiro RC, Krynetski EY, Pui CH Evans WE . Intolerance to mercaptopurine therapy related to heterozygosity at the thiopurine methyltransferase gene locus J Natl Cancer Inst 1999 91: 2001–2008
Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH . High incidence of secondary brain tumours after radiotherapy and antimetabolites Lancet 1999 354: 34–39
Relling MV, Yanishevski Y, Nemec J, Evans WE, Boyett JM, Behn FG, Pui CH . Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia Leukemia 1998 12: 346–352
Thomsen JB, Schroder H, Kristinsson J, Madsen B, Szumlanski C, Weinshilboum R, Andersen JB, Schmiegelow . Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells Cancer 1999 86: 1080–1086
Krynetski EY, Evans WE . Pharmacogenetics of cancer therapy: getting personal Am Hum Genet 1998 63: 11–16
Kitchen BJ, Moser A, Lowe E, Balis FM, Widemann B, Anderson L, Strong J, Blaney SM, Berg SL, O'Brien M, Adamson PC . Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine J Pharmacol Exp Ther 1999 2: 870–874
Krynetski EY, Krynetskaia NF, Yanishevski Y, Evans WE . Methylation of mercaptopurine, thioguanine, and their nucleotide metabolites by heterologously expressed human thiopurine S-methyltransferase Mol Pharmacol 1995 6: 1141–1147
Acknowledgements
This work was supported by Aberdeen Royal Infirmary Endowments, Cancer Center Core grant CAZ1765, by NIH grants R37 CA 36401 and R01 CA51001, and American Lebanese Syrian Associated Charities (ALSAC). The efforts of Kate Smith in manuscript preparation are greatly appreciated.
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McLeod, H., Krynetski, E., Relling, M. et al. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 14, 567–572 (2000). https://doi.org/10.1038/sj.leu.2401723
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DOI: https://doi.org/10.1038/sj.leu.2401723
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