The effect of thiopurine drugs on DNA methylation in relation to TPMT expression

Biochemical Pharmacology
Linda A HogarthSally A Coulthard

Abstract

The thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well-established agents for the treatment of leukaemia but their main modes of action are controversial. Thiopurine methyltransferase (TPMT) metabolises thiopurine drugs and influences their cytotoxic activity. TPMT, like DNA methyltransferases (DNMTs), transfers methyl groups from S-adenosylmethionine (SAM) and generates S-adenosylhomocysteine (SAH). Since SAM levels are dependent on de novo purine synthesis (DNPS) and the metabolic products of 6-TG and 6-MP differ in their ability to inhibit DNPS, we postulated that 6-TG compared to 6-MP would have differential effects on changes in SAM and SAH levels and global DNA methylation, depending on TPMT status. To test this hypothesis, we used a human embryonic kidney cell line with inducible TPMT. Although changes in SAM and SAH levels occurred with each drug, decrease in global DNA methylation more closely reflected a decrease in DNMT activity. Inhibition was influenced by TPMT for 6-TG, but not 6-MP. The decrease in global methylation and DNMT activity with 6-MP, or with 6-TG when TPMT expression was low, were comparable to 5-aza-2'-deoxycytidine. However, this was not reflected in changes in methylation at...Continue Reading

References

Jan 1, 1995·Advances in Enzyme Regulation·R De AbreuL Van den Heuvel
Apr 5, 2002·Nature·Ina RheeBert Vogelstein
Jun 18, 2002·Molecular Pharmacology·Sally A CoulthardAndrew G Hall
Oct 7, 2003·Oncogene·Rainer Claus, Michael Lübbert
Nov 5, 2004·Cellular and Molecular Life Sciences : CMLS·A HermannA Jeltsch
May 18, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kapil N Bhalla
Jun 25, 2005·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Rita CastroIsabel Tavares de Almeida
Oct 20, 2005·Journal of the National Cancer Institute·Frank Lyko, Robert Brown
Feb 18, 2006·Nature Reviews. Drug Discovery·Christine B Yoo, Peter A Jones
Feb 24, 2006·Nature Reviews. Cancer·Stephen B Baylin, Joyce E Ohm
Mar 3, 2006·Cancer Research·Carlo StresemannFrank Lyko
Jul 25, 2006·Advances in Enzyme Regulation·Fabio SpadaHeinrich Leonhardt
Oct 11, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kim AppletonRobert Brown

❮ Previous
Next ❯

Citations

Feb 19, 2009·European Journal of Human Genetics : EJHG·David GurwitzDolores Ibarreta
Feb 2, 2011·Molecular Cancer Therapeutics·Sally A CoulthardLinda A Hogarth
Sep 13, 2012·Pharmacogenomics·Ann K DalySally Coulthard
Jan 26, 2010·Biochemical Pharmacology·Alan Kambiz FotoohiFreidoun Albertioni
Dec 1, 2017·Antioxidants & Redox Signaling·María A Pajares, Dolores Pérez-Sala
Jun 10, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sally A CoulthardChris P F Redfern
Sep 1, 2016·Neuro-oncology Practice·Benjamin Purow
Nov 5, 2019·Frontiers in Genetics·Marcelo L RibeiroGaël Roué

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Epigenetics & Metabolism (Keystone)

Epigenetic changes are present and dysregulated in many cancers, including DNA methylation, non-coding RNA segments and post-translational protein modifications. The epigenetic changes may or may not provide advantages for the cancer cells. This feed focuses on the relationship between cell metabolism, epigenetics and tumor differentiation.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis