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

• Published in: Cancer chemotherapy and pharmacology Vol. 74; no. 4; pp. 757 - 763
• Main Authors: Carlsson, Göran, Odin, Elisabeth, Gustavsson, Bengt, Wettergren, Yvonne
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.10.2014; Springer; Springer Nature B.V
• Subjects: Aged; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antineoplastic agents; Biological and medical sciences; Cancer and Oncology; Cancer och onkologi; Cancer Research; Chemotherapy, Adjuvant - methods; Chromatography, High Pressure Liquid - methods; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Dihydrouracil Dehydrogenase (NADP) - metabolism; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Drug-Related Side Effects and Adverse Reactions - etiology; Drug-Related Side Effects and Adverse Reactions - prevention & control; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Kirurgi; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; Oncology; Original Article; Pharmacology. Drug treatments; Pharmacology/Toxicology; Predictive Value of Tests; Reproducibility of Results; Risk Assessment; Saliva - metabolism; Sex Factors; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Surgery; Tumors; Uracil - analogs & derivatives; Uracil - metabolism; Dihydropyrimidine dehydrogenase; Dihydrouracil; Uracil; Saliva; Colorectal cancer; 5-FU; Antineoplastic agent; Biological fluid; Rectal disease; Toxicity; Intestinal disease; Fluorouracil; Human; Enzyme; Fluoropyrimidine derivatives; Transferases; Enzyme inhibitor; ); Malignant tumor; Dihydropyrimidine dehydrogenase (NADP; Thymidylate synthase; Colonic disease; Chemotherapy; Treatment; Antimetabolic; Methyltransferases; Pyrimidine derivatives; Digestive diseases; Oxidoreductases; Cancer
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-014-2553-2

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 (UH 2 ) 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 UH 2 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 UH 2 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 UH 2 concentrations in saliva were 5.0 ± 6.8 and 5.0 ± 4.0 nmol/ml, respectively. The UH 2 /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 UH 2 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.