In an NBC News article titled” A quick test could protect against fatal chemo overdose, yet few doctors use it,” Arthur Allen tells the story of a 70-year-old woman who tragically died after an overdose of a chemotherapy drug. The drug she was prescribed is a pill called capecitabine which is chemically similar to the intravenous chemotherapy drug known as 5-FU or fluorouracil. While these drugs are used commonly in cancer treatment, those who are deficient in an enzyme that metabolizes the drugs can experience a slew of unpleasant symptoms or, in Carol Rosen’s case, die.

In his article, Allen states that the reason patients die from chemotherapy drugs is because the drugs stay in the body for hours instead of being quickly metabolized. In a review titled” Testing for Dihydropyrimidine Dehydrogenase Deficiency to Individualize 5-Fluorouracil Therapy,” the authors go into more detail about the way that the molecular mechanisms work for an overdose to happen. Genetic factors are a big contributor to the risk of developing severe toxicity to 5-FU. This was confirmed by researchers through advanced pedigree analyses (Diasio & Offer, 2022). The enzyme necessary for metabolizing the drugs is dihydropyrimidine dehydrogenase (DPD) and two deleterious variants were identified in the gene that encodes DPD. The genes segregate independently and have an autosomal codominant inheritance pattern (Diasio & Offer, 2022). Since then, many other variants have been identified after more clinical testing. In individuals with DPD deficiency, it causes the catabolic pathway to shift toward anabolism, potentially causing severe toxicity. However, not all of those with the deficiency will be at severe risk if they use the topical forms of the chemotherapy drugs. Arthur Allen did a good job of simplifying the way that the overdose is caused, but Diasio and Offer went more into depth about what happens at a cellular level. 

Due to the correlation between DPD deficiency and 5-FU toxicity, it is important to give doctors ways to identify DPD deficiency so that adjustments to the dosage of the medication can be made. There are both phenotypic tests and genotype-based tests that can be performed to test for DPD deficiency. Genotypic tests have higher accuracy and have been used frequently in European countries (Diasio & Offer, 2022). After her mother’s death, Carol Rosen’s daughter urged the hospital to implement genetic testing before prescribing fluoropyrimidine. The hospital quickly adopted a system to test patients and around 50 patients were detected with the deficiency within 10 months (Allen, 2024). Multiple different tests can be used; some check for eleven potentially dangerous variants, whereas others only screen for eight or four. An important factor in these genetic tests is that they are not one size fits all and different tests may be necessary for different ancestries. Most of the clinical studies have been conducted in Europe but different variants of the enzyme deficiency have been found in African American individuals that did not appear in European patients (Diasio & Offer, 2022). A man named Dr. Anil Kapoor died as a result of fluoropyrimidine poisoning. Kapoor was tested for four variants of the deleterious gene, but he carried a variant of the gene associated with South Asian descent that is not covered in the European-based genetic tests (Allen, 2024). While tests that screen for hundreds of variants are out there, they can be expensive, and getting results back can take longer. Some doctors have pushed back on mandatory testing, stating that the results can be unclear and lead to undertreatment of patients. Fluorouracil is not the only drug that has been prescribed to people who lack the enzyme to properly metabolize it. An anti-blood clotting medication called clopidogrel was marketed as safe for Native Hawaiians while more than 50% of them lack an important enzyme that processes clopidogrel.

References

Allen, A. (2022, March 27). A quick test could protect against fatal chemo overdose, yet few doctors use it. NBCNews.com. https://www.nbcnews.com/health/cancer/quick-test-protect-fatal-chemo-overdose-yet-cancer-doctors-use-rcna144664

Diasio, B. Offer, S. Testing for Dihydropyrimidine Dehydrogenase Deficiency to Individualize 5-Fluorouracil Therapy. MDPI; https://www.mdpi.com/2072-6694/14/13/3207 (2022).