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William E Evans - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on Mercaptopurine toxicity
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Laura J Janke, Jun J Yang, John D Schuetz, William E Evans, Mary V RellingAbstract:Purpose Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in Mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with Mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.
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genetic polymorphism of inosine triphosphate pyrophosphatase influences Mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine s methyl transferase status
Expert Opinion on Drug Safety, 2010Co-Authors: Gabriele Stocco, Kristine R Crews, William E EvansAbstract:Importance of the field: Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on Mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when Mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in Mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which Mercaptopurine doses are individualized based on TPMT genotype.Area covered in this review: In this review, we summarize the knowledge available a...
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genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of Mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Mary V Relling, Gabriele Stocco, Meyling Cheok, Kristine R Crews, Thierry Dervieux, Deborah L French, Wenjian Yang, C Cheng, William E EvansAbstract:The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on Mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl Mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of Mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose Mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which Mercaptopurine doses are individualized on the basis of TPMT genotype.
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differential effects of targeted disruption of thiopurine methyltransferase on Mercaptopurine and thioguanine pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Mary V RellingAbstract: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. [Cancer Res 2007;67(10):4965–72]
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Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Ching-hon Pui, Mary V RellingAbstract: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.
Mary V Relling - One of the best experts on this subject based on the ideXlab platform.
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Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on Mercaptopurine toxicity
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Laura J Janke, Jun J Yang, John D Schuetz, William E Evans, Mary V RellingAbstract:Purpose Mercaptopurine plays a pivotal role in treatment of acute lymphoblastic leukemia (ALL) and autoimmune diseases, and inter-individual variability in Mercaptopurine tolerance can influence treatment outcome. Thiopurine methyltransferase (TPMT) and multi-drug resistant Protein 4 (MRP4) have both been associated with Mercaptopurine toxicity in clinical studies, but their relative contributions remain unclear.
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genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of Mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Mary V Relling, Gabriele Stocco, Meyling Cheok, Kristine R Crews, Thierry Dervieux, Deborah L French, Wenjian Yang, C Cheng, William E EvansAbstract:The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on Mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl Mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of Mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose Mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which Mercaptopurine doses are individualized on the basis of TPMT genotype.
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differential effects of targeted disruption of thiopurine methyltransferase on Mercaptopurine and thioguanine pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Mary V RellingAbstract: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. [Cancer Res 2007;67(10):4965–72]
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Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Ching-hon Pui, Mary V RellingAbstract: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.
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differing contribution of thiopurine methyltransferase to Mercaptopurine versus thioguanine effects in human leukemic cells
Cancer Research, 2001Co-Authors: Thierry Dervieux, Eugene Y Krynetski, Javier G Blanco, Elio F Vanin, Martine F Roussel, Mary V RellingAbstract:Thioguanine and Mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylMercaptopurine nucleotides from thioguanine and Mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of Mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P 99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of Mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylMercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.
Gabriele Stocco - One of the best experts on this subject based on the ideXlab platform.
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pacsin2 polymorphism influences tpmt activity and Mercaptopurine related gastrointestinal toxicity
Human Molecular Genetics, 2012Co-Authors: Gabriele Stocco, Kristine R Crews, Wenjian Yang, William E Thierfelder, Giuliana Decorti, Margherita Londero, Raffaella Franca, Marco Rabusin, Maria Grazia Valsecchi, Cheng ChengAbstract:Treatment-related toxicity can be life-threatening and is the primary cause of interruption or discontinuation of chemotherapy for acute lymphoblastic leukemia (ALL), leading to an increased risk of relapse. Mercaptopurine is an essential component of continuation therapy in all ALL treatment protocols worldwide. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) are known to have a marked effect on Mercaptopurine metabolism and toxicity; however, some patients with wild-type TPMT develop toxicity during Mercaptopurine treatment for reasons that are not well understood. To identify additional genetic determinants of Mercaptopurine toxicity, a genome-wide analysis was performed in a panel of human HapMap cell lines to identify trans-acting genes whose expression and/or single-nucleotide polymorphisms (SNPs) are related to TPMT activity, then validated in patients with ALL. The highest ranking gene with both mRNA expression and SNPs associated with TPMT activity in HapMap cell lines was protein kinase C and casein kinase substrate in neurons 2 (PACSIN2). The association of a PACSIN2 SNP (rs2413739) with TPMT activity was confirmed in patients and knock-down of PACSIN2 mRNA in human leukemia cells (NALM6) resulted in significantly lower TPMT activity. Moreover, this PACSIN2 SNP was significantly associated with the incidence of severe gastrointestinal (GI) toxicity during consolidation therapy containing Mercaptopurine, and remained significant in a multivariate analysis including TPMT and SLCO1B1 as covariates, consistent with its influence on TPMT activity. The association with GI toxicity was also validated in a separate cohort of pediatric patients with ALL. These data indicate that polymorphism in PACSIN2 significantly modulates TPMT activity and influences the risk of GI toxicity associated with Mercaptopurine therapy.
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genetic polymorphism of inosine triphosphate pyrophosphatase influences Mercaptopurine metabolism and toxicity during treatment of acute lymphoblastic leukemia individualized for thiopurine s methyl transferase status
Expert Opinion on Drug Safety, 2010Co-Authors: Gabriele Stocco, Kristine R Crews, William E EvansAbstract:Importance of the field: Although genetic polymorphisms in the gene encoding human thiopurine methyltransferase (TPMT) are known to have a marked effect on Mercaptopurine metabolism and toxicity, there are many patients with wild-type TPMT who develop toxicity. Furthermore, when Mercaptopurine dosages are adjusted in patients who are heterozygous at the TPMT locus, there are still some patients who develop toxicity for reasons that are not fully understood. Therefore, we recently studied the effects of a common polymorphism in another gene encoding an enzyme involved in Mercaptopurine metabolism (SNP rs1127354 in inosine-triphospate-pyrophosphatase, ITPA), showing that genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of febrile neutropenia following combination chemotherapy of acute lymphoblastic leukemia (ALL) in which Mercaptopurine doses are individualized based on TPMT genotype.Area covered in this review: In this review, we summarize the knowledge available a...
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genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of Mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Mary V Relling, Gabriele Stocco, Meyling Cheok, Kristine R Crews, Thierry Dervieux, Deborah L French, Wenjian Yang, C Cheng, William E EvansAbstract:The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on Mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl Mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of Mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose Mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which Mercaptopurine doses are individualized on the basis of TPMT genotype.
Matthias Schwab - One of the best experts on this subject based on the ideXlab platform.
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Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Ching-hon Pui, Mary V RellingAbstract: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.
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differential effects of targeted disruption of thiopurine methyltransferase on Mercaptopurine and thioguanine pharmacodynamics
Cancer Research, 2007Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Mary V RellingAbstract: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. [Cancer Res 2007;67(10):4965–72]
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Thiopurine Treatment in Inflammatory Bowel Disease
Clinical Pharmacokinetics, 2007Co-Authors: Alexander Teml, Klaus Herrlinger, Elke Schaeffeler, Ulrich Klotz, Matthias SchwabAbstract:This review summarises clinical pharmacological aspects of thiopurines in the treatment of chronic inflammatory bowel disease (IBD). Current knowledge of pharmacogenetically guided dosing is discussed for individualisation of thiopurine therapy, particularly to avoid severe adverse effects. Both azathioprine and Mercaptopurine are pro-drugs that undergo extensive metabolism. The catabolic enzyme thiopurine S -methyltransferase (TPMT) is polymorphically expressed, and currently 23 genetic variants have been described. On the basis of an excellent phenotype-genotype correlation for TPMT, genotyping has become a safe and reliable tool for determination of a patient’s individual phenotype. Thiopurine-related adverse drug reactions are frequent, ranging from 5% up to 40%, in both a dose-dependent and -independent manner. IBD patients with low TPMT activity are at high risk of developing severe haematotoxicity if pharmacogenetically guided dosing is not performed. Based on several cost-benefit analyses, assessment of TPMT activity is recommended prior to thiopurine therapy in patients with IBD. The underlying mechanisms of azathioprine/Mercaptopurine-related hepatotoxicity, pancreatitis and azathioprine intolerance are still unknown. Although the therapeutic response appears to be related to 6-thioguanine nucleotide (6-TGN) concentrations above a threshold of 230–260 pmol per 8 × 10^8 red blood cells, at present therapeutic drug monitoring of 6-TGN can be recommended only to estimate patients’ compliance. Drug-drug interactions between azathioprine/Mercaptopurine and aminosalicylates, diuretics, NSAIDs, warfarin and infliximab are discussed. The concomitant use of allopurinol without dosage adjustment of azathioprine/Mercaptopurine leads to clinically relevant severe haematotoxicity due to elevated thiopurine levels. Several studies indicate that thiopurine therapy in IBD during pregnancy is safe. Thus, azathioprine/Mercaptopurine should not be withdrawn in strictly indicated cases of pregnant IBD patients. However, breastfeeding is contraindicated during azathioprine/Mercaptopurine therapy. Use of azathioprine/Mercaptopurine for induction and maintenance of remission in corticosteroid-dependent or corticosteroid-refractory IBD, particularly Crohn’s disease, is evidence based. To improve response rates in thiopurine therapy of IBD, comprehensive analyses including metabolic patterns and genome-wide profiling in patients with azathioprine/Mercaptopurine treatment are required to identify novel candidate genes.
Thierry Dervieux - One of the best experts on this subject based on the ideXlab platform.
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genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of Mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia
Clinical Pharmacology & Therapeutics, 2009Co-Authors: Mary V Relling, Gabriele Stocco, Meyling Cheok, Kristine R Crews, Thierry Dervieux, Deborah L French, Wenjian Yang, C Cheng, William E EvansAbstract:The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on Mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl Mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of Mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose Mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of Mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which Mercaptopurine doses are individualized on the basis of TPMT genotype.
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differing contribution of thiopurine methyltransferase to Mercaptopurine versus thioguanine effects in human leukemic cells
Cancer Research, 2001Co-Authors: Thierry Dervieux, Eugene Y Krynetski, Javier G Blanco, Elio F Vanin, Martine F Roussel, Mary V RellingAbstract:Thioguanine and Mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylMercaptopurine nucleotides from thioguanine and Mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of Mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P 99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of Mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylMercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.