Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy.

Abstract

PURPOSE:

5-fluorouracil (5-FU) competes with uracil (Ura) as a substrate for dihydropyrimidine dehydrogenase (DPD). Low DPD activity impairs breakdown of Ura to dihydrouracil (UH₂) and is associated with toxicity during 5-FU-based chemotherapy. Calculation of the 5-FU dose is based on body surface area, and new tools are needed to individualize treatment. The aim of study was to measure Ura and UH₂ in saliva of patients with colorectal cancer and relate levels to treatment-induced toxicity.

METHODS:

Saliva was collected from 73 patients with stage III colorectal cancer prior to adjuvant 5-FU-based treatment. Ura and UH₂ were analyzed by a column-switching HPLC method. Toxicity was evaluated before each treatment cycle and the highest grade was noted at end of treatment.

RESULTS:

Toxicity was more common and severe among women compared with men. The Ura and UH₂ concentrations in saliva were 5.0 ± 6.8 and 5.0 ± 4.0 nmol/ml, respectively. The UH₂/Ura ratio was lower in women compared with men (1.2 ± 1.0 and 2.2 ± 2.5, respectively, p = 0.0026). Patients who needed to reduce the drug dose during treatment (or terminate treatment) due to toxicity had a lower ratio (1.3 ± 0.85) compared to patients who completed treatment without dose reduction (4.1 ± 4.3, p < 0.0001).

CONCLUSION:

Sampling of saliva is a quick, noninvasive, safe and painless process that gives information about patients Ura and UH₂ levels prior to chemotherapeutical treatment. This information may be useful in order to predict and prevent occurrence of treatment-related toxicities which otherwise may limit drug administration.

• Authors: Göran Carlsson, Elisabeth Odin, Bengt Gustavsson, Yvonne Wettergren
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 74 Issue 4 Pg. 757-63 (Oct 2014) ISSN: 1432-0843 [Electronic] Germany
• PMID: 25102934 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• dihydrouracil
• Uracil
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil

Topics

• Aged
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Chemotherapy, Adjuvant (methods)
• Chromatography, High Pressure Liquid (methods)
• Colorectal Neoplasms (drug therapy, metabolism)
• Dihydrouracil Dehydrogenase (NADP) (metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Drug-Related Side Effects and Adverse Reactions (etiology, prevention & control)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Predictive Value of Tests
• Reproducibility of Results
• Risk Assessment
• Saliva (metabolism)
• Sex Factors
• Uracil (analogs & derivatives, metabolism)