Cytotoxicity of Thiopurine Drugs in Patients with Inflammatory Bowel Disease

Overview

Journal Toxics

Date 2022 Apr 21

PMID 35448412

Authors

Oliwia Zakerska-Banaszak

Liliana Lykowska-Szuber

Michal Walczak

Joanna Zuraszek

Aleksandra Zielinska

Marzena Skrzypczak-Zielinska

Affiliations

Soon will be listed here.

Abstract

The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn's disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines' benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.

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References

Duley J, Somogyi A, Martin J . The future of thiopurine pharmacogenomics. Pharmacogenomics. 2012; 13(14):1549-52. DOI: 10.2217/pgs.12.140. View

Gonzalez-Lama Y, Bermejo F, Lopez-Sanroman A, Garcia-Sanchez V, Esteve M, Cabriada J . Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients. Aliment Pharmacol Ther. 2011; 34(5):544-54. DOI: 10.1111/j.1365-2036.2011.04756.x. View

Moriyama T, Yang Y, Nishii R, Ariffin H, Liu C, Lin T . Novel variants in and thiopurine intolerance in children with acute lymphoblastic leukemia from diverse ancestry. Blood. 2017; 130(10):1209-1212. PMC: 5606007. DOI: 10.1182/blood-2017-05-782383. View

Harmand P, Solassol J . Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT. Genes (Basel). 2020; 11(10). PMC: 7602704. DOI: 10.3390/genes11101212. View

Weinshilboum R, Sladek S . Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980; 32(5):651-62. PMC: 1686086. View

RAPPAPORT H . Replication of the base pair 6-thioguanine/5-methyl-2-pyrimidine with the large Klenow fragment of Escherichia coli DNA polymerase I. Biochemistry. 1993; 32(12):3047-57. DOI: 10.1021/bi00063a016. View

Pelin M, Genova E, Fusco L, Marisat M, Hofmann U, Favretto D . Pharmacokinetics and pharmacodynamics of thiopurines in an in vitro model of human hepatocytes: Insights from an innovative mass spectrometry assay. Chem Biol Interact. 2017; 275:189-195. DOI: 10.1016/j.cbi.2017.08.009. View

Shih D, Nguyen M, Zheng L, Ibanez P, Mei L, Kwan L . Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther. 2012; 36(5):449-58. DOI: 10.1111/j.1365-2036.2012.05206.x. View

Colombel J, Sandborn W, Reinisch W, Mantzaris G, Kornbluth A, Rachmilewitz D . Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010; 362(15):1383-95. DOI: 10.1056/NEJMoa0904492. View

10.

Cornish J, Wirthgen E, Dabritz J . Biomarkers Predictive of Response to Thiopurine Therapy in Inflammatory Bowel Disease. Front Med (Lausanne). 2020; 7:8. PMC: 7000528. DOI: 10.3389/fmed.2020.00008. View

11.

You C, Dai X, Yuan B, Wang Y . Effects of 6-thioguanine and S6-methylthioguanine on transcription in vitro and in human cells. J Biol Chem. 2012; 287(49):40915-23. PMC: 3510796. DOI: 10.1074/jbc.M112.418681. View

12.

DHaens G, Reinisch W, Colombel J, Panes J, Ghosh S, Prantera C . Five-year Safety Data From ENCORE, a European Observational Safety Registry for Adults With Crohn's Disease Treated With Infliximab [Remicade®] or Conventional Therapy. J Crohns Colitis. 2016; 11(6):680-689. DOI: 10.1093/ecco-jcc/jjw221. View

13.

Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T . Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009; 24(7):1258-64. DOI: 10.1111/j.1440-1746.2009.05917.x. View

14.

Biemans V, Savelkoul E, Gabriels R, Simsek M, Dijkstra G, Pierik M . A comparative analysis of tioguanine versus low-dose thiopurines combined with allopurinol in inflammatory bowel disease patients. Aliment Pharmacol Ther. 2020; 51(11):1076-1086. PMC: 7318327. DOI: 10.1111/apt.15730. View

15.

Schaeffeler E, Jaeger S, Klumpp V, Yang J, Igel S, Hinze L . Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry. Genet Med. 2019; 21(9):2145-2150. PMC: 6752748. DOI: 10.1038/s41436-019-0448-7. View

16.

Lichtenstein G, Feagan B, Cohen R, Salzberg B, Diamond R, Langholff W . Drug therapies and the risk of malignancy in Crohn's disease: results from the TREAT™ Registry. Am J Gastroenterol. 2014; 109(2):212-23. DOI: 10.1038/ajg.2013.441. View

17.

Chande N, Patton P, Tsoulis D, Thomas B, MacDonald J . Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2015; (10):CD000067. PMC: 9578512. DOI: 10.1002/14651858.CD000067.pub3. View

18.

Ungaro R, Brenner E, Gearry R, Kaplan G, Kissous-Hunt M, Lewis J . Effect of IBD medications on COVID-19 outcomes: results from an international registry. Gut. 2020; 70(4):725-732. PMC: 8136807. DOI: 10.1136/gutjnl-2020-322539. View

19.

Andoh A, Kawahara M, Imai T, Tatsumi G, Inatomi O, Kakuta Y . Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease. J Gastroenterol. 2021; 56(10):881-890. DOI: 10.1007/s00535-021-01805-z. View

20.

Chen S, Tan W, Sutiman N, Lim C, Lee S, Leong W . An intronic FTO variant rs16952570 confers protection against thiopurine-induced myelotoxicities in multiethnic Asian IBD patients. Pharmacogenomics J. 2019; 20(3):505-515. DOI: 10.1038/s41397-019-0126-9. View