Contribution of the β-ureidopropionase (UPB1) gene alterations to the development of fluoropyrimidine-related toxicity

Background: an impairment of the 5-fluorouracil (5-fu) catabolic pathway,represented by alterations in the dihydropyrimidine dehydrogenase (dpyd) gene,is considered a crucial factor contributing to the development of 5-fu-related toxicity. the β-ureidopropionase (bup1) enzyme catalyzes the final step in the 5-fu catabolic pathway; however,alterations in the upb1 gene coding for the bup1 enzyme have not yet been analyzed in fluoropyrimidine (fp)-treated patients suffering from 5-fu-related toxicity. methods: we have performed a mutation analysis of the entire coding sequence of upb1 based on denaturing high-performance liquid chromatography in 113 cancer patients treated by fp-containing regimes. these patients included 67 individuals suffering from severe 5-fu-related toxicity and 46 individuals with excellent tolerance of chemotherapy. results: nine upb1 variants were detected in the subpopulation of patients with severe toxicity,including a novel mutation affecting the coding sequence (c.872-873+11del13). an analysis of upb1 variants on 5-fu-related toxicity in the population of all analyzed patients revealed an association between the c.-80c>g (rs2070474) variant and gastrointestinal toxicity. a strong positive correlation was found between the carriers of the c.-80gggenotype and the development of severe (grade 3-4) mucositis (or = 7.5; 95% ci = 2.60 - 21.60; p = 0.0002). conclusion: our results suggest that upb1 variants may contribute to the development of 5-fu-related toxicity in some fp-treated patients; however,the role of upb1 alterations is probably less significant than that of dpyd alterations. copyright © 2012 by institute of pharmacology polish academy of sciences.