The long term objective of this project is to improve 5-fluorouracil (5- FU) chemotherapy in cancer patients by better understanding the recently reported genetic polymorphism of the pyrimidine catabolic enzyme, dihydropyrimidine dehyrogenase (also known as dihydrouracil dehydrogenase, dihydrothymine dehydrogenase, DPD, EC 22.214.171.124) and its role in determining 5-FU toxicity in patients. Studies in our laboratory have demonstrated the critical role that DPD has in regulating 5-FU catabolism and hence 5-FU available for anabolism. Since 5-FU anabolism determines toxicity, it is hypothesized that decreased DPD activity would increase 5-FU toxicity. In preliminary studies, several patients with severe 5-FU toxicity were identified who were profoundly deficient in DPD activity compared to controls. Family studies demonstrated that DPD activity is inherited as an autosomal recessive. Subsequent studies of patients with moderate toxicity revealed DPD activity in an intermediate range similar to the levels detected in the children or parents (heterozygotes) in the family studies of the profound deficient patients. We propose the following: Spec.
Aim 1) Determine population distribution of DPD activity and frequency of genetic deficiency of DPD in the cancer and non-cancer patient population; Spec.
Aim 2) Determine in a prospective study the relationship between DPD activity and 5-FU toxicity;
Spec Aim 3) Determine biochemical properties of DPD from peripheral blood mononuclear cells of normal and deficient individuals. Comparison of DPD from deficient patients with DPD from normal individuals should provide insight into the mechanism of genetic polymorphism of DPD. Theses studies should be useful in the future in predicting which patients may be susceptible to severe 5-FU toxicity, permitting modification of drug dose before chemotherapy.
|Lee, Adam M; Shi, Qian; Alberts, Steven R et al. (2016) Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: NCCTG N0147 (Alliance). Pharmacogenet Genomics 26:133-7|
|Lee, Adam M; Shi, Qian; Pavey, Emily et al. (2014) DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147). J Natl Cancer Inst 106:|
|Offer, Steven M; Butterfield, Gabriel L; Jerde, Calvin R et al. (2014) microRNAs miR-27a and miR-27b directly regulate liver dihydropyrimidine dehydrogenase expression through two conserved binding sites. Mol Cancer Ther 13:742-51|
|Offer, S M; Lee, A M; Mattison, L K et al. (2013) A DPYD variant (Y186C) in individuals of african ancestry is associated with reduced DPD enzyme activity. Clin Pharmacol Ther 94:158-66|
|Thomas, Holly R; Ezzeldin, Hany H; Guarcello, Vincenzo et al. (2008) Genetic regulation of beta-ureidopropionase and its possible implication in altered uracil catabolism. Pharmacogenet Genomics 18:25-35|
|Saif, M Wasif; Syrigos, Kostas; Mehra, Ranee et al. (2007) DIHYDROPYRIMIDINE DEHYDROGENASE DEFICIENCY (DPD) IN GI MALIGNANCIES: EXPERIENCE OF 4-YEARS. Pak J Med Sci Q 23:832-839|
|Thomas, Holly R; Ezzeldin, Hany H; Guarcello, Vincenzo et al. (2007) Genetic regulation of dihydropyrimidinase and its possible implication in altered uracil catabolism. Pharmacogenet Genomics 17:973-87|
|Saif, M W; Ezzeldin, Hany; Vance, Katisha et al. (2007) DPYD*2A mutation: the most common mutation associated with DPD deficiency. Cancer Chemother Pharmacol 60:503-7|
|Zhang, Xue; Soong, Richie; Wang, Kangsheng et al. (2007) Suppression of DPYD expression in RKO cells via DNA methylation in the regulatory region of the DPYD promoter: a potentially important epigenetic mechanism regulating DPYD expression. Biochem Cell Biol 85:337-46|
|Saif, Muhammad Wasif; Mattison, Lori; Carollo, Tom et al. (2006) Dihydropyrimidine dehydrogenase deficiency in an Indian population. Cancer Chemother Pharmacol 58:396-401|
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