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Dihydropyrimidine dehydrogenase activity and the IVS14+1G>A mutation in patients developing 5FU-related toxicity

Nicolas Magné1, Marie-Christine Etienne-Grimaldi, Laurent Cals

  • 1Institut Gustave Roussy, Villejuif, France.

British Journal of Clinical Pharmacology
|March 6, 2007
PubMed
Abstract

Insights

Lower dihydropyrimidine dehydrogenase (DPD) activity correlates with increased 5-fluorouracil (5FU) toxicity intensity. Some patients with normal DPD activity still experienced severe, life-threatening 5FU toxicity, indicating complex risk factors.

Area of Science:

  • Pharmacogenomics
  • Clinical Toxicology
  • Cancer Therapeutics

Background:

  • 5-fluorouracil (5FU) is a cornerstone chemotherapy agent.
  • Dihydropyrimidine dehydrogenase (DPD) is the primary enzyme responsible for 5FU catabolism.
  • DPD deficiency can lead to increased 5FU exposure and severe toxicity.

Observation:

  • Retrospective analysis of 131 patients with 5FU toxicity.
  • Lower DPD activity levels (10-504 pmol min(-1) mg(-1)) were significantly associated with higher toxicity grades (P < 0.01).
  • Nine patients (eight women) experienced toxicity-related deaths, all exhibiting significantly lower DPD activity compared to other patients.

Findings:

  • A significant inverse correlation exists between DPD enzyme activity and the severity of 5FU-induced toxicity.
  • While reduced DPD activity is a major risk factor, two deceased patients had normal DPD activity, suggesting other contributing factors.
  • The IVS14+1G>A mutation, tested in 93 patients, was found in two with non-lethal toxicity, questioning its utility in predicting severe outcomes.

Implications:

  • DPD activity testing may be crucial for stratifying 5FU toxicity risk, but normal DPD activity does not preclude severe adverse events.
  • Clinical management of 5FU should consider DPD status alongside other potential risk modifiers.
  • Further research is needed to elucidate mechanisms of 5FU toxicity in patients with normal DPD activity and to identify predictive biomarkers beyond DPD genotype.

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