5-Fluorouracil and DPYD

5-Fluorouracil (Adrucil ®, others and generic products) is a drug used to treat many types of cancer by shrinking tumors. It works best on solid tumors found in the breast, colon, rectum, and gastrointestinal tract, among others. This medication is most commonly given as an intravenous (IV) infusion during a course of chemotherapy.

The specific effects of 5-fluorouracil on the body are rather complex. Essentially, 5-fluorouracil prevents an enzyme involved in the process of making and repairing DNA from working properly. If the tumor cells are unable to make new DNA, they can no longer divide and reproduce. This leads to cell death and tumor shrinkage.

The primary gene of interest is DPYD, which is related to potential adverse effects of 5-fluorouracil. DPYD is a gene that tells the body to produce drug metabolizing enzymes that break down 5-fluorouracil. When the DPYD gene is altered, the drug is broken down as rapidly or at all. This means that patients are exposed to higher concentrations of 5-fluorouracil which may lead to severe adverse effects.

If not broken down and eliminated over time, 5-fluorouracil is highly toxic. Patients with changes in the DPYD gene or lower levels of the gene may experience more side effects because most of the drug remains intact.

Identifying an individual's DPYD gene will allow cancer treatment to be individualized. This allows for the most appropriate dose of 5-fluorouracil can be determined to improve the chance of a positive outcome while limiting the potential side effects.

A 45 year old man, Jordan, is diagnosed with brain cancer and prescribed 5-flurouracil to help shrink a tumor. Jordan asks his doctor about possible side effects and is told about the risk of toxicity if Jordan has an alteration in his DPYD gene. Jordan does not want to do the genetic testing because he wants to get started on his medication. Shortly after starting the 5-fluorouracil, Jordan has uncontrolled diarrhea with dehydration and goes to the emergency room. The hospital, suspecting toxicity, decides to perform the genetic test and discovers that Jordan has altered DPYD function. This made Jordan unable to eliminate 5-fluorouracil from his body as efficiently as those with normal functioning DPYD. After recovering from the toxic event, Jordan is prescribed a lower dose of 5-fluorouracil.

After getting diagnosed with neck cancer, Gabby is prescribed 5-fluorouracil to help shrink her cancerous tumor. Since the diagnosis, Gabby has been looking at the internet to see possible side effects of her many medications and asks her doctor about DPYD. After hearing from her doctor the possibility of toxicity and maybe death if she has non-functioning DPYD, Gabby decides to undergo a genetic test to determine if she is high risk for having a toxic event. The test results show that Gabby has DPYD that is less functioning than the majority of the population and that this could increase her risk at normal doses. The physician prescribes her a lower dose and she has the potential benefit of 5-fluorouracil therapy with less risks.

DPD genetic testing does not completely rule out the risks of taking 5-fluorouracil, 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.

The links below provide access to important articles and information relative to 5-fluorouracil. The links are to external websites and will be checked regularly for consistency.

• 5-fluorouracil Prescribing Information
• 5-fluorouracil Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: 5-fluorouracil

DailyMed [Internet]. Bethesda (MD): U.S. National Library of Medicine; c1993-2012. Fluorouracil; [cited 2012 Oct 23]; [about 4 screens]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8eff167f-203a-4a81-b2fc-d8773bc3555e/.

PharmGKB [Internet]. Stanford (CA): U.S. Department of Health and Human Services; c2001-2017. Fluorouracil; [cited 2012 Oct 19]; [about 5 screens]. Available from: https://www.pharmgkb.org/chemical/PA128406956#tabOverview/.

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Yang CG, Ciccolini J, Blesius A, et al. DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity. Cancer Chemotherapy Pharmacology. 2011 Jan;67(1):49-56.