title: Pretherapeutic uracil and dihydrouracil levels in saliva of colorectal cancer patients are associated with toxicity during adjuvant 5-fluorouracil-based chemotherapy.
abstract: OBJECTIVE
  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).
  
  
  CONCLUSIONS
  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.affiliation: Department of Surgery, Institute of Clinical Sciences, Sahlgrenska University Hospital/Östra, the Sahlgrenska Academy at University of Gothenburg, 41685, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Odin
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wettergren
mesh_terms: D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D017024:Chemotherapy, Adjuvant / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D018570:Risk Assessment; D012463:Saliva / Q000378:metabolism*; D012737:Sex Factors; D014498:Uracil / Q000031:analogs & derivatives* / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C007419:dihydrouracil; D014498:Uracil; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil