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Journal of Crohn's & Colitis Apr 2018Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients... (Review)
Review
Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.
Topics: Azathioprine; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infliximab; Mercaptopurine; Neoplasms; Risk Factors; Thioguanine
PubMed: 29293971
DOI: 10.1093/ecco-jcc/jjx181 -
Expert Opinion on Drug Discovery Sep 20186-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target... (Review)
Review
6-Mercaptopurine (6-MP) and 6-thioguanine (6-TG), two anticancer drugs, have high systemic toxicity due to a lack of target specificity. Therefore, increasing target selectivity should improve drug safety. Areas covered: The authors examined the hypothesis that new prodrug designs based upon mechanisms of kidney-selective toxicity of trichloroethylene would reduce systemic toxicity and improve selectivity to kidney and tumor cells. Two approaches specifically were investigated. The first approach was based upon bioactivation of trichloroethylene-cysteine S-conjugate by renal cysteine S-conjugate β-lyases. The prodrugs obtained were kidney-selective but exhibited low turnover rates. The second approach was based on the toxic mechanism of trichloroethylene-cysteine S-conjugate sulfoxide, a Michael acceptor that undergoes rapid addition-elimination reactions with biological thiols. Expert opinion: Glutathione-dependent Michael addition-elimination reactions appear to be an excellent strategy to design highly efficient anticancer drugs. Targeting glutathione could be a promising approach for the development of anticancer prodrugs because cancer cells usually upregulate glutathione biosynthesis and/or glutathione S-transferases expression.
Topics: Animals; Antineoplastic Agents; Drug Design; Glutathione; Glutathione Transferase; Humans; Kidney; Mercaptopurine; Molecular Targeted Therapy; Neoplasms; Prodrugs; Thioguanine
PubMed: 30101640
DOI: 10.1080/17460441.2018.1508207 -
Cancer Discovery Nov 2022Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of...
UNLABELLED
Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.
SIGNIFICANCE
Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.
Topics: Humans; Mercaptopurine; 5'-Nucleotidase; Drug Resistance, Neoplasm; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; Recurrence
PubMed: 35984649
DOI: 10.1158/2159-8290.CD-22-0010 -
Gut Oct 2023Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several... (Review)
Review
Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.
Topics: Humans; Thioguanine; Off-Label Use; Gastroenterology; Inflammatory Bowel Diseases; Netherlands; Azathioprine; Mercaptopurine; Immunosuppressive Agents
PubMed: 37380330
DOI: 10.1136/gutjnl-2023-329679 -
Genomics, Proteomics & Bioinformatics Apr 2017Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in... (Review)
Review
Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2-3years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.
Topics: Adolescent; Antineoplastic Agents; Child; Child, Preschool; Female; Humans; Maintenance Chemotherapy; Male; Mercaptopurine; Methotrexate; Pharmacogenetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28391009
DOI: 10.1016/j.gpb.2016.11.003 -
Journal of Crohn's & Colitis Jul 2023
Topics: Humans; Mercaptopurine; Colitis, Ulcerative; Azathioprine; Immunosuppressive Agents; Immunologic Factors
PubMed: 37141302
DOI: 10.1093/ecco-jcc/jjad062 -
World Journal of Gastroenterology Dec 2016The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical... (Review)
Review
The use of thiopurines in inflammatory bowel disease (IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor (anti-TNF) agents, and maintenance of remission and post-operative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.
Topics: Azathioprine; Colitis, Ulcerative; Crohn Disease; Drug Therapy, Combination; Gastrointestinal Agents; History, 20th Century; History, 21st Century; Humans; Immunosuppressive Agents; Infliximab; Maintenance Chemotherapy; Mercaptopurine; Remission Induction; Tumor Necrosis Factor-alpha
PubMed: 28028358
DOI: 10.3748/wjg.v22.i46.10103 -
Alimentary Pharmacology & Therapeutics Oct 2020
Topics: Adolescent; Azathioprine; Child; Denmark; Female; Humans; Mercaptopurine; Outcome Assessment, Health Care; Pregnancy; Tumor Necrosis Factor-alpha
PubMed: 33105977
DOI: 10.1111/apt.16017 -
International Journal of Molecular... May 2020Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent...
Flavonoids are natural phenolic compounds, which are the active ingredients in several dietary supplements. It is well-known that some flavonoid aglycones are potent inhibitors of the xanthine oxidase (XO)-catalyzed uric acid formation . However, the effects of conjugated flavonoid metabolites are poorly characterized. Furthermore, the inhibition of XO-catalyzed 6-mercaptopurine oxidation is an important reaction in the pharmacokinetics of this antitumor drug. The inhibitory effects of some compounds on xanthine vs. 6-mercaptopurine oxidation showed large differences. Nevertheless, we have only limited information regarding the impact of flavonoids on 6-mercaptopurine oxidation. In this study, we examined the interactions of flavonoid aglycones and some of their conjugates with XO-catalyzed xanthine and 6-mercaptopurine oxidation . Diosmetin was the strongest inhibitor of uric acid formation, while apigenin showed the highest effect on 6-thiouric acid production. Kaempferol, fisetin, geraldol, luteolin, diosmetin, and chrysoeriol proved to be similarly strong inhibitors of xanthine and 6-mercaptopurine oxidation. While apigenin, chrysin, and chrysin-7-sulfate were more potent inhibitors of 6-mercaptopurine than xanthine oxidation. Many flavonoids showed similar or stronger (even 5- to 40-fold) inhibition of XO than the positive control allopurinol. Based on these observations, the extremely high intake of flavonoids may interfere with the elimination of 6-mercaptopurine.
Topics: Allopurinol; Catalysis; Dose-Response Relationship, Drug; Flavonoids; Mercaptopurine; Oxidation-Reduction; Xanthine; Xanthine Oxidase
PubMed: 32380641
DOI: 10.3390/ijms21093256 -
Journal of Pharmacy Practice Aug 2023Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It... (Review)
Review
Macrophage activation syndrome is a life-threatening syndrome of uncontrolled immune activation with variable clinical presentation making early diagnosis difficult. It is often manifested by the development of multi-organ failure due to systemic inflammatory response. Patients with ulcerative colitis (UC) on purine antimetabolites are at high risk for severe myelosuppression due to the mechanism of thiopurine toxicity which potentially contributes to the development of macrophage activation syndrome. We present a case of a 39-year-old woman with a 2-year history of UC previously treated with 6-mercaptopurine (6-MP) and recent COVID-19 infection, who was admitted to our emergency department for C. difficile infection and subsequently developed macrophage activation syndrome. This case report also raises the question of whether abrupt discontinuation of 6-MP may have contributed to the worsening of the patient's symptoms of underlying hemophagocytic lymphohistiocytosis (HLH) and her rapid deterioration. Both macrophage activation syndrome and COVID-19 infection can produce a large number of pro-inflammatory cytokines termed "cytokine storm," but a pro-inflammatory cytokine panel breakdown helps to differentiate between the two. Our case report emphasizes the importance of close monitoring of patients on purine antimetabolite therapy who present with signs and symptoms of systemic toxicity.
Topics: Humans; Female; Adult; Macrophage Activation Syndrome; Mercaptopurine; Clostridioides difficile; COVID-19; Lymphohistiocytosis, Hemophagocytic
PubMed: 35341387
DOI: 10.1177/08971900221081617