Tegafur and DPYD

Nick Newman, Pharm.D. Candidate; Elise Smith, Pharm.D. Candidate; Isabel Cwikla, Pharm.D. Candidate; Sean Bennett, Pharm.D. Candidate; Jennifer Perez, Pharm.D. Candidate

About the Drug

Tegafur is a chemotherapy drug which is often used in combination with uracil. Tegafur is a prodrug, meaning it is inactive until the body converts it to an active compound. This active compound is fluorouracil, which carries out the actual therapeutic effects of the medication. Fluorouracil functions by interfering with the creation of DNA and RNA, which are two of the absolutely necessary elements in replication of healthy as well as cancerous cells. Fluorouracil effectively limits cell growth, which is why it is used for the treatment of cancer, a disease of excess cell growth. Cancers this drug can be used to treat include colorectal, liver, lung, bladder, breast, stomach, and cervical.

About the Gene

The active compound obtained from tegafur, fluorouracil, is broken down by an enzyme known as dihydropyrimidine dehydrogenase (DPD). The DPYD gene is responsible for the production of the DPD enzyme, and is the primary concern of genomic treatment. Variations in this gene among different patients can alter the effects of the drug. Individuals can have either functioning or non-functioning copies of this gene.

About the Drug-Gene Interaction

Non-functioning copies of the DPYD gene mean that fluorouracil is unable to be broken down, resulting in higher levels of fluorouracil in the body. These increased levels of fluorouracil can lead to severe or even possibly fatal adverse effects. If an individual has two functional copies, the drug can be administered as normal. A person with one functional and one non-functional copy will need a reduced dose; the recommendation is to start at 50% of the normal dose. Someone with two non-functional copies of the gene should avoid tegafur completely and use an alternative treatment.

Drug-Gene Interaction Example

Virginia is a 50-year-old African American female patient who appeared at clinic with severe abdominal discomfort. She stated changes in bowel habits, stool consistency, and noticed blood in stool. When asked when was the last time she has seen a doctor, she stated that she had not seen a doctor in about 5 years. Virginia had an adenomatous colorectal polyp, which was removed by colonoscopy 5 years ago and has avoided going to the doctor since. A guaiac-based fecal occult blood test (gFOBT) was ordered and Virginia was diagnosed with colorectal cancer shortly after. The physician asked if Virginia would like to do a genetic test before starting her on the first cycle of chemotherapy using 5-fluorouracil and she refused.

After her first cycle was complete, Virginia complained of severe diarrhea. After further evaluation, she was experiencing Grade 3 and 4 myelotoxicity and gastrointestinal toxicity, especially mucositis and diarrhea. After full recovery from side effects, Virginia was started on tegafur-uracil (UFT) and leucovorin with a 40% dose reduction. Genotype testing was done on the patient and the results showed a partial dihydropyrimidine dehydrogenase deficiency with the heterozygous alleles DPYD*2A*1. Virginia did not have any occurrence of grade 3 or 4 toxicity. The predominant toxicity after switching to UFT and leucovorin was grade 1 and 2 nausea, vomiting and diarrhea, which were controlled by conventional clinical measures.

Gene sequencing does not completely rule out the risks of acute toxicities related to chemotherapy medications, nor does it guarantee the medications will work. However, 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 tegafur. The links are to external websites and will be checked regularly for consistency.

Sources of Information

Byfield JE, Hornbeck CL, Frankel SS, et al. Relevance of the pharmacology of oral tegafur to its use as a 5-FU prodrug. Cancer Treat Rep. 1985;69:645-52.

Cubero DIG, Cruz FM, Santi P, Silva ID, and Giglio A. Tegafur–uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle. Ther Adv Med Oncol. 2012 Jul;4(4):167-72.

Deenen MJ, Cats A, Beijnen JH, and Schellens JHM. Standard-dose tegafur-uracil (UFT) is not a safe alternative in partial dihydropyrimidine dehydrogenase-deficient patients. Ther Adv Med Oncol. 2013 Jan;5(1):91-2.

Lexicomp Online [Internet]. Hudson (OH): Wolters Kluwer. Tegafur; [2015 Oct. 14; 2015 Dec. 4]; Available from: http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/7847

Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015 Dec;16(16):1639-50.

M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. Pharmacogenomics Knowledge for Personalized Medicine. Clin Pharmacol Ther. 2012;92(4):414-17.

PharmGKB [Internet]. PharmGKB; c2001-2016. Tegafur; [updated 2017 Mar 16; cited 2015 Dec 8]; [about 4 screens]. Available from: https://www.pharmgkb.org/chemical/PA452620.