Thioguanine and TPMT

Emily Loudermilk, Pharm.D. Candidate; Sean Bennett, Pharm.D. Candidate; Isabel Cwikla, Pharm.D. Ca

 

About the Drug

Thioguanine is a drug that prevents the growth and spread of certain tumor cells. It is most commonly used in acute myelogenous leukemia. This drug works by interfering with the production of DNA precursors, so it belongs to the class of medications called purine analog antimetabolites. When DNA is being formed, thioguanine is incorporated in the place of a DNA base. This results in blocking of the formation and metabolism of DNA bases.

About the Gene

The gene of interest with this drug is Thiopurine S-Methyltransferase (TPMT), which is an enzyme that breaks down purine drugs, such as thioguanine, to inactive metabolites. Without this gene, purine drugs would remain in the body for a longer period of time, causing significant damage to healthy cells in the immune system and bone marrow, in addition to tumor cells.

About the Drug-Gene Interaction

Changes to the DNA sequence that codes for the TPMT enzyme can cause changes in the activity of the enzyme. Normally functioning enzymes result in thioguanine being metabolized to the inactive form before it causes too much damage to healthy cells. People who have decreased enzyme activity accumulate increased amounts of the drug, which can lead to severe adverse effects. These individuals should be on lower doses of thioguanine to prevent significant damage to the immune system and bone marrow.

Drug-Gene Interaction Example

Ann is a 6-year-old Asian American diagnosed with acute myelogenous leukemia. She has been undergoing chemotherapy and achieved remission recently. She is about to be started on a combination of thioguanine and cytarabine for remission. Her physician has asked her parents if they would like to undergo genotypic testing for Ann before starting her remission therapy. Due to the cost, her parents opted out of the genotype test. At her next visit, the doctor requested a complete blood count (CBC) and the lab results showed that Ann was undergoing severe myelosuppression. A genetic test was done shortly after and Ann was heterozygous for a nonfunctional TPMT allele: TPMT *1*2 which means she is an intermediate metabolizer for thioguanine, which caused high levels of the metabolite and led to the myelosuppression.

Later that year, the physician saw a similar patient, 8-year-old Jay, whose parents did opt to have a genotype test done for TPMT alleles. Jay’s genotype was found to be heterozygous for nonfunctional TPMT with the 1*4* alleles. Fortunately, Jay was able to have his dose for thioguanine reduced by 50%, which in turn avoided high concentrations of the drug in his body so he did not experience any adverse side effects of the drug.

TPMT genetic testing does not completely rule out the risks of taking thioguanine, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

Provider Information

The links below provide access to important articles and information relative to thioguanine. The links are to external websites and will be checked regularly for consistency.

Sources of Information

American Cancer Society [Internet]. American Cancer Society; c2017. Prognostic factors in childhood leukemia (ALL or AML); [updated 2016 Feb 3; cited 2015 Dec 23]; [about 5 screens]. Available from: http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemia-prognostic-factors.

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Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman’s: The pharmacological basis of therapeutics [Internet]. 12th ed. New York: McGraw-Hill; 2011 [cited 2015 Dec 4]. Available from: http://0-accesspharmacy.mhmedical.com.polar.onu.edu/book.aspx?bookid=1613.

Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2017. Thioguanine; [cited 2015 Dec 4]. Available from: http://0-www.clinicalpharmacology-ip.com.polar.onu.edu/Forms/drugoptions.aspx?cpnum=603&n=Thioguanine%2c+6-TG&t=0.

Dipiero J, Teng K, Hicks JK. Should thiopurine methyltransferase (TPMT) activity be determined before prescribing azathioprine, mercaptopurine, or thioguanine? Cleve Clin J Med. 2015 Jul;82(7):409-13.

Genetics Home Reference [Internet]. Bethesda (MD): U.S. Department of Health and Human Services; 2015 Nov 30; TPMT; [2015 Dec 4]; [about 4 screens]. Available from: http://ghr.nlm.nih.gov/gene/TPMT

Lexicomp [Internet]. Hudson (OH):Wolters Kluwer Clinical Drug Information Inc. Thioguanine; [updated 2015 Oct 10; cited 2015 Dec 4]; [about 13 screens]. Available from: http://www.crlonline.com/lco/action/doc/retrieve/ docid/patch_f/7757

PharmGKB [Internet]. PharmGKB; c2001-2016. Thioguanine; [updated 2017 Mar 15; cited 2015 Dec 4]; [about 3 screens]. Available from: https://www.pharmgkb.org/chemical/PA451663.

Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther. 2012 Oct;92(4):414-7.