The value of dihydrouracil/uracil plasma ratios in predicting 5-fluorouracil-related toxicity in colorectal cancer patients.

Abstract

This study investigated the relationship between the dihydrouracil/uracil (UH(2)/U) plasma ratio, a surrogate marker of dihydropyrimidine dehydrogenase (DPD) activity, and 5-fluorouracil (5-FU)-related early toxicity. Plasma UH(2)/U ratios were determined in 68 colorectal cancer patients and 100 healthy controls. A cut-off value indicative of DPD deficiency was calculated using receiver operator characteristics. Patients experiencing toxicity were screened for the DPD G-to-A point mutation within the 5'-splicing donor site of intron 14 (IVS14+1G>A). Overall, 24/68 patients (35%) experienced toxicity (all grades) and abnormal UH(2)/U ratios were demonstrated in 21/24 (87.5%) patients. Drug concentrations up to 130 times the recommended level were found in 13/24 (54%) patients experiencing toxicity. One patient experiencing toxicity was a heterozygous carrier of the IVS14+1G>A mutation. A low UH(2)/U plasma ratio had a sensitivity of 0.87 and specificity of 0.93 for predicting 5-FU-induced toxicity. Systematic detection of DPD-deficient patients using the UH(2)/U ratio could optimize 5-FU-based chemotherapy and minimize life-threatening toxicity.

• Authors: M H Kristensen, P Pedersen, J Mejer
• Journal: The Journal of international medical research (J Int Med Res) 2010 Jul-Aug Vol. 38 Issue 4 Pg. 1313-23 ISSN: 0300-0605 [Print] England
• PMID: 20926004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA Splice Sites
• dihydrouracil
• Uracil
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Colorectal Neoplasms (blood, drug therapy)
• DNA Mutational Analysis
• Dihydrouracil Dehydrogenase (NADP) (genetics)
• Female
• Fluorouracil (adverse effects, blood, therapeutic use)
• Humans
• Introns (genetics)
• Male
• Middle Aged
• RNA Splice Sites (genetics)
• Uracil (analogs & derivatives, blood)