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Mary V Relling - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics
    Cancer Research, 2007
    Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Mary V Relling
    Abstract:

    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]

  • Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics
    Cancer Research, 2007
    Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Ching-hon Pui, Mary V Relling
    Abstract:

    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.

  • Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.
    Clinical pharmacology and therapeutics, 2003
    Co-Authors: Thierry Dervieux, William E Evans, Michael L Hancock, Gaston K Rivera, John T Sandlund, Raul C Ribeiro, Ching-hon Pui, James M. Boyett, Mary V Relling
    Abstract:

    Background: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, Tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. Methods: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m2 over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m2, or high dose, 1 g/m2 intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. Results: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 ± 14.7 μmol/L versus 23.5 ± 18.0 μmol/L, P < .001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 ± 0.66 pmol/5 × 106 cells versus 7.4 ± 15.2 pmol/5 × 106 cells, P < .001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 ± 13.5 μmol/L versus 3.8 ± 2.5 μmol/L, P = .029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% ± 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% ± 35%) compared with those in patients receiving mercaptopurine alone (P < .0001). Conclusion: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine. Clinical Pharmacology & Therapeutics (2003) 73, 506–516; doi: 10.1016/S0009-9236(03)00063-8

  • differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells
    Cancer Research, 2001
    Co-Authors: Thierry Dervieux, Javier G Blanco, Elio F Vanin, Martine F Roussel, Eugene Y Krynetski, Mary V Relling
    Abstract:

    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 50 = 1.10± 0.12 μm versus 0.55 ± 0.19 μm; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC 50 = 0.52 ± 0.20 μm versus 1.50 ± 0.23 μm; P versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 ± 282 versus 1515 ± 183 pmol/5 × 10 6 cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 ± 34 versus 27 ± 10 pmol/5 × 10 6 cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P versus 7.2 ± 2.0%; P versus 174 ± 77 pmol/5 × 10 6 cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT.

  • differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells
    Cancer Research, 2001
    Co-Authors: Thierry Dervieux, Javier G Blanco, Elio F Vanin, Martine F Roussel, Eugene Y Krynetski, Mary V Relling
    Abstract:

    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.

Chris J. J. Mulder - One of the best experts on this subject based on the ideXlab platform.

  • sustained effectiveness safety and therapeutic drug monitoring of Tioguanine in a cohort of 274 ibd patients intolerant for conventional therapies
    Alimentary Pharmacology & Therapeutics, 2019
    Co-Authors: Melek Simsek, Margien L. Seinen, Chris J. J. Mulder, Debbie S Deben, Carmen S Horjus, Melanie V Benard, Birgit I Lissenbergwitte, Hans J C Buiter, Matthijs Van Luin, Dennis R Wong
    Abstract:

    Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged Tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of Tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d Tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with Tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P < 0.05). Conclusions: Long-term Tioguanine therapy for at least 12 months was effective in 51% and well tolerated as a maintenance treatment for IBD in about 70% of patients. Adverse events were common, but mainly mild or moderate. 6-Thioguanine nucleotide threshold concentration ≥ 700 pmol/8×108RBC is proposed as target level with higher odds for clinical effectiveness.

  • Sustained effectiveness, safety and therapeutic drug monitoring of Tioguanine in a cohort of 274 IBD patients intolerant for conventional therapies
    Alimentary pharmacology & therapeutics, 2019
    Co-Authors: Melek Simsek, Margien L. Seinen, Chris J. J. Mulder, Debbie S Deben, Carmen S Horjus, Melanie V Benard, Hans J C Buiter, Matthijs Van Luin, Birgit I. Lissenberg-witte, Dennis R Wong
    Abstract:

    Background: Tioguanine (or thioguanine) is an alternative drug for IBD patients who fail prior conventional immunomodulating therapy. Aim: To report effectiveness, safety and therapeutic drug monitoring in a cohort of patients with prolonged Tioguanine maintenance therapy. Methods: In this nationwide, multicentre study, medical records of Tioguanine- using IBD patients were retrospectively reviewed. Response to therapy was defined as clinical effectiveness without (re)initiation of corticosteroids, concurrent biological therapy or surgical intervention. All adverse events that occurred during the follow-up were listed and graded according to the common terminology criteria (CTC). Results: Two hundred and seventy-four patients (female 63%, Crohn's disease in 68%) were included with median treatment duration of 51 months, 1567 patient-years of follow-up and median 20 mg/d Tioguanine dosage. Tioguanine was tolerated in 79%, clinical effectiveness at 6 months was documented in 66% and sustained clinical effectiveness during 12 months in 51% of patients. Forty-one per cent of patients developed adverse events: 5% were graded as severe. Adverse events comprised infection requiring hospitalisation in three and skin cancer in eight patients (two melanomas). Asymptomatic nodular regenerative hyperplasia of the liver occurred in two out of 52 patients with liver biopsies (3.8%) and portal hypertension in three whereof one potentially associated with Tioguanine (0.4%). Clinical effectiveness was correlated with 6-thioguanine nucleotide threshold concentrations >682 pmol/8×108RBC (P 

  • Biochemical efficacy of Tioguanine in autoimmune hepatitis: a retrospective review of practice in the Netherlands
    Alimentary pharmacology & therapeutics, 2018
    Co-Authors: Floris F. Van Den Brand, Nanne K H De Boer, Chris J. J. Mulder, Carin M J Van Nieuwkerk, Bart J. Verwer, Ynto S. De Boer, Elisabeth Bloemena, Christine M. Bakker, Jan M. Vrolijk, Joost P.h. Drenth
    Abstract:

    BACKGROUND: Azathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid-sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens. AIM: To evaluate retrospectively the tolerability and efficacy of Tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes. METHODS: Records of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first-line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G. RESULTS: No serious adverse events occurred in patients treated with TG during a median follow-up of 18 months (range 1-194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty-eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non-response (n = 2). TG was effective in all AIH patients as first-line maintenance treatment. CONCLUSION: In our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy.

  • Safety of Tioguanine During Pregnancy in Inflammatory Bowel Disease
    Journal of Crohn's & colitis, 2015
    Co-Authors: Sophie A. Van Den Berg, Ad A. Van Bodegraven, Frank Hoentjen, Marjon A. De Boer, Andrea E. Van Der Meulen-de Jong, Jeroen M. Jansen, Maurice G. Russel, Nofel Mahmmod, C. Janneke Van Der Woude, Chris J. J. Mulder
    Abstract:

    Background and Aims: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine Tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. Methods: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. Results: In all, 13 patients [77% Crohn’s disease, 23% ulcerative colitis] used TG [median dose 18g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. Conclusions: This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy.

  • Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment.
    Journal of Crohns & Colitis, 2012
    Co-Authors: Dirk P. Van Asseldonk, Nanne K H De Boer, Margien L. Seinen, Ad A. Van Bodegraven, Chris J. J. Mulder
    Abstract:

    Abstract Background and aims High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Methods A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. Results Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21mg (9–24)) was 23weeks (6–96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p Conclusion Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients.

William E Evans - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of targeted disruption of thiopurine methyltransferase on mercaptopurine and thioguanine pharmacodynamics
    Cancer Research, 2007
    Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Mary V Relling
    Abstract:

    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]

  • Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics
    Cancer Research, 2007
    Co-Authors: Christine Hartford, Erick Vasquez, Gerard Grosveld, Jerold E. Rehg, Matthias Schwab, Mathew J Edick, William E Evans, Ching-hon Pui, Mary V Relling
    Abstract:

    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.

  • Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia.
    Clinical pharmacology and therapeutics, 2003
    Co-Authors: Thierry Dervieux, William E Evans, Michael L Hancock, Gaston K Rivera, John T Sandlund, Raul C Ribeiro, Ching-hon Pui, James M. Boyett, Mary V Relling
    Abstract:

    Background: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, Tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. Methods: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m2 over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m2, or high dose, 1 g/m2 intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. Results: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 ± 14.7 μmol/L versus 23.5 ± 18.0 μmol/L, P < .001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 ± 0.66 pmol/5 × 106 cells versus 7.4 ± 15.2 pmol/5 × 106 cells, P < .001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 ± 13.5 μmol/L versus 3.8 ± 2.5 μmol/L, P = .029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% ± 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% ± 35%) compared with those in patients receiving mercaptopurine alone (P < .0001). Conclusion: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine. Clinical Pharmacology & Therapeutics (2003) 73, 506–516; doi: 10.1016/S0009-9236(03)00063-8

  • mercaptopurine therapy intolerance and heterozygosity at the thiopurine s methyltransferase gene locus
    Journal of the National Cancer Institute, 1999
    Co-Authors: Mary V Relling, Eugene Y Krynetski, Michael L Hancock, Gaston K Rivera, John T Sandlund, Raul C Ribeiro, William E Evans
    Abstract:

    Background: 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. Methods: 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. Results: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 ◊ 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 homozygousdeficient (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. Conclusion: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait. [J Natl Cancer Inst 1999;91:2001‐8]

  • genetic polymorphism of thiopurine s methyltransferase clinical importance and molecular mechanisms
    Pharmacogenetics, 1996
    Co-Authors: Eugene Y Krynetski, Thrina Loennechen, John D Schuetz, Charles R Yates, Michael Y Fessing, Mary V Relling, William E Evans
    Abstract:

    Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurines such as mercaptopurine and thioguanine. TPMT activity exhibits genetic polymorphism, with about 1 in 300 inheriting TPMT-deficiency as an autosomal recessive trait. If treated with standard dosages of thiopurines, TPMT-

Ad A. Van Bodegraven - One of the best experts on this subject based on the ideXlab platform.

  • Safety of Tioguanine During Pregnancy in Inflammatory Bowel Disease
    Journal of Crohn's & colitis, 2015
    Co-Authors: Sophie A. Van Den Berg, Ad A. Van Bodegraven, Frank Hoentjen, Marjon A. De Boer, Andrea E. Van Der Meulen-de Jong, Jeroen M. Jansen, Maurice G. Russel, Nofel Mahmmod, C. Janneke Van Der Woude, Chris J. J. Mulder
    Abstract:

    Background and Aims: Conventional thiopurine [azathioprine and mercaptopurine] treatment during pregnancy in patients with inflammatory bowel disease [IBD] is considered to be safe; however data on the safety and teratogenicity of the non-conventional thiopurine Tioguanine [TG] in pregnant IBD patients are lacking. We aim to describe the safety and teratogenicity of TG treatment during pregnancy in IBD patients. Methods: This was a retrospective, multicentre descriptive case series of female IBD patients using TG during pregnancy. Data on disease and medication history, pregnancy complications, pregnancy outcome, mode of delivery, preterm birth, birthweight, congenital abnormalities, laboratory signs of myelosuppression or hepatotoxicity, and 6-thioguaninenucleotide [6-TGN] concentrations in mother and neonate were collected. Results: In all, 13 patients [77% Crohn’s disease, 23% ulcerative colitis] used TG [median dose 18g/day] during pregnancy; 19 pregnancies, including 1 twin pregnancy, were included. Spontaneous abortion occurred in three pregnancies. In 7 of the 16 ongoing pregnancies a caesarean section was performed. One neonate had a mild congenital abnormality [distal shaft hypospadias]. In the singleton pregnancies, the median birthweight was 3410g at a median of gestational age of 39 weeks. No preterm birth [< 37 weeks] or low birthweight [< 2500 g] was observed in the singleton newborns. In the twin pregnancy an induction of labour was performed at 35 + 1 weeks of gestation because of pre-eclampsia. Both neonates had a low birthweight. Conclusions: This relatively small case series supports safe use of TG in pregnant IBD patients. Still, consideration should be given to the indication and continuation of TG during pregnancy.

  • Tioguanine in the treatment of refractory coeliac disease--a single centre experience.
    Alimentary pharmacology & therapeutics, 2012
    Co-Authors: Greetje J. Tack, Ad A. Van Bodegraven, Dirk P. Van Asseldonk, R.l.j. Van Wanrooij, C J J Mulder
    Abstract:

    Summary Background Refractory coeliac disease type I is a complicated form of coeliac disease characterised by primary or secondary resistance to a gluten-free diet with persisting or reoccurring intestinal villous atrophy and symptoms of malabsorption. Besides corticosteroids, azathioprine has been advocated for the treatment of refractory coeliac disease type I. However, Tioguanine (TG) might be better tolerated and more efficacious owing to a simpler metabolism towards bioactivation. Aim To evaluate tolerability and effectiveness of the nonconventional thiopurine derivative TG in refractory coeliac disease type I. Methods Refractory coeliac disease type I patients treated with TG between June 2001 and November 2010 with a follow-up period of at least 1 year were included. Adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response were evaluated at baseline and during follow-up. Results Twelve adult refractory coeliac disease type I patients were included. The median TG treatment duration was 14 months. Ten patients tolerated TG treatment on the long term, whereas two patients withdrew treatment due to adverse events. No nodular regenerative hyperplasia of the liver was observed. During follow-up clinical and histological response was observed in 83% and 78%, respectively. Corticosteroid dependency decreased by 50%. Conclusion Tioguanine appears to be a convenient drug for the treatment of refractory coeliac disease type I based on higher histological and similar clinical response rates as compared with historical conventional therapies.

  • Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment.
    Journal of Crohns & Colitis, 2012
    Co-Authors: Dirk P. Van Asseldonk, Nanne K H De Boer, Margien L. Seinen, Ad A. Van Bodegraven, Chris J. J. Mulder
    Abstract:

    Abstract Background and aims High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Methods A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. Results Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21mg (9–24)) was 23weeks (6–96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p Conclusion Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients.

  • Safety and efficacy of the immunosuppressive agent 6-Tioguanine in murine model of acute and chronic colitis
    BMC gastroenterology, 2011
    Co-Authors: Miloslav Kverka, Bindia Jharap, Nanne K H De Boer, Ad A. Van Bodegraven, Pavel Rossmann, Helena Tlaskalova-hogenova, Klara Klimesova, René M. Vos, Milan Lukas, Chris J. J. Mulder
    Abstract:

    Background Oral thiopurines are effective and widely used in treatment of inflammatory bowel disease (IBD) in humans, although their use is limited due the development of adverse events. Here, we examine the efficacy and toxicity of oral treatment with 6-Tioguanine (6-TG) and azathioprine (AZA) in a murine model of IBD.

  • Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD
    Nature Clinical Practice Gastroenterology & Hepatology, 2007
    Co-Authors: Nanne K H De Boer, Bindia Jharap, Peer De Graaf, Ad A. Van Bodegraven, Chris J. J. Mulder
    Abstract:

    The pharmacological activity of thiopurine therapy is in part mediated by the specific metabolite 6-thioguanosine 5′-triphosphate, which induces apoptosis of activated T cells The complex pharmacology and metabolism of thiopurines have been partly elucidated, leading to the development of novel strategies (e.g. metabolite measurements and thiopurine S-methyltransferase determination) to optimize thiopurine therapy Frequent hematological and biochemical monitoring, including complete blood counts and liver tests, remain the best-accepted methods for toxicity screening The frequency of nodular regenerative hyperplasia as an adverse event during thiopurine therapy is probably underestimated—the induction of this hepatotoxic feature might be thiopurine-dose-dependent or metabolite-level dependent A maintenance dosage of 6-thioguanine not exceeding 25 mg daily can be considered rescue therapy exclusively for patients with IBD who are intolerant of, or resistant to, standard therapies; 6-thioguanine should only be administered in a clinical trial setting under close (hepatotoxicity) surveillance, at least until more toxicity data are available Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5′-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S -methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides. Improved knowledge of the complex pharmacology, metabolism, mechanism of action, and toxicity profile of thiopurines has guided the development of strategies to improve pharmacotherapy in patients with IBD. This Review discusses the clinical implications of these developments, such as reducing the risk of adverse events (e.g. myelodepression and hepatotoxicity) by genetic screening, metabolite level characterization, and dose reductions.

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  • Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis.
    Alimentary pharmacology & therapeutics, 2013
    Co-Authors: Y. S. De Boer, C J J Mulder, N. K. H. De Boer, N. M. F. Van Gerven, Gerd Bouma, C.m.j. Van Nieuwkerk
    Abstract:

    Summary Background Ten percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-Tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease. Aim To describe the effect of adding allopurinol to low-dose thiopurine therapy in patients with AIH with intolerance or nonresponse to normal thiopurine dosages due to a skewed metabolism. Methods We describe the clinical efficacy and tolerability of allopurinol–thiopurine combination therapy with allopurinol 100 mg and low-dose thiopurine (25–33% of the original dosage) in eight AIH patients with a skewed thiopurine metabolism. Patients were switched because of dose-limiting intolerance (n = 3), nonresponse (n = 3) or loss of response (n = 2) to conventional thiopurine treatment. Results All eight patients showed biochemical improvement with a reduction in median alanine aminotransferase (ALT) levels of 62 U/L at start to 35 U/L at 1 month (P = 0.03). This clinical benefit was sustained in seven patients. Allopurinol–thiopurine combination therapy effectively bypassed thiopurine side effects in four of five patients. Median 6-Tioguanine nucleotides levels increased from 100 to 200 pmol/8 × 108 red blood cells (RBC) at 3 months (P = 0.04). Median 6-MMP levels decreased in all patients from 6090 to 175 pmol/8 × 108 RBC (P = 0.01). Conclusion Allopurinol safely and effectively optimises thiopurine therapy in patients with autoimmune hepatitis with intolerance and/or nonresponse due to an unfavourable thiopurine metabolism.

  • Tioguanine in the treatment of refractory coeliac disease--a single centre experience.
    Alimentary pharmacology & therapeutics, 2012
    Co-Authors: Greetje J. Tack, Ad A. Van Bodegraven, Dirk P. Van Asseldonk, R.l.j. Van Wanrooij, C J J Mulder
    Abstract:

    Summary Background Refractory coeliac disease type I is a complicated form of coeliac disease characterised by primary or secondary resistance to a gluten-free diet with persisting or reoccurring intestinal villous atrophy and symptoms of malabsorption. Besides corticosteroids, azathioprine has been advocated for the treatment of refractory coeliac disease type I. However, Tioguanine (TG) might be better tolerated and more efficacious owing to a simpler metabolism towards bioactivation. Aim To evaluate tolerability and effectiveness of the nonconventional thiopurine derivative TG in refractory coeliac disease type I. Methods Refractory coeliac disease type I patients treated with TG between June 2001 and November 2010 with a follow-up period of at least 1 year were included. Adverse events, laboratory values, 6-thioguanine nucleotide concentrations and rates of both clinical and histological response were evaluated at baseline and during follow-up. Results Twelve adult refractory coeliac disease type I patients were included. The median TG treatment duration was 14 months. Ten patients tolerated TG treatment on the long term, whereas two patients withdrew treatment due to adverse events. No nodular regenerative hyperplasia of the liver was observed. During follow-up clinical and histological response was observed in 83% and 78%, respectively. Corticosteroid dependency decreased by 50%. Conclusion Tioguanine appears to be a convenient drug for the treatment of refractory coeliac disease type I based on higher histological and similar clinical response rates as compared with historical conventional therapies.

  • drug insight pharmacology and toxicity of thiopurine therapy in patients with ibd
    Nature Clinical Practice Gastroenterology & Hepatology, 2007
    Co-Authors: Nanne K H De Boer, Bindia Jharap, Peer De Graaf, Adriaan A Van Bodegraven, C J J Mulder
    Abstract:

    Improved knowledge of the complex pharmacology, metabolism, mechanism of action, and toxicity profile of thiopurines has guided the development of strategies to improve pharmacotherapy in patients with IBD. This Review discusses the clinical implications of these developments, such as reducing the risk of adverse events (e.g. myelodepression and hepatotoxicity) by genetic screening, metabolite level characterization, and dose reductions. Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5′-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.

  • Why measure thiopurine methyltransferase activity? Direct administration of 6-thioguanine might be the alternative for 6-mercaptopurine or azathioprine
    Gut, 2001
    Co-Authors: D. De Jong, C J J Mulder, A A Van Sorge
    Abstract:

    Editor,—6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective in inflammatory bowel disease (IBD), mainly by their active 6-thioguanine (6-TG) metabolites. Efficacy and also myelotoxicity of 6-MP and AZA seem to be related to the 6-TG levels achieved. Instead of activation to 6-thioguanine nucleotides, 6-MP and AZA can be inactivated to 6-methylmercaptopurine (6-MMP) by the enzyme thiopurine methyltransferase (TPMT). High interindividual variability in TPMT activity is known. Therefore, measuring TPMT activity could be …