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Circadian variation in intestinal dihydropyrimidine dehydrogenase (DPD) expression: a potential mechanism for benefits of 5FU chrono-chemotherapy.

Authors: Abolmaali, K  Balakrishnan, A  Stearns, AT  Rounds, J  Rhoads, DB  Ashley, SW  Tavakkolizadeh, A 
Citation: Abolmaali K, etal., Surgery. 2009 Aug;146(2):269-73.
Pubmed: (View Article at PubMed) PMID:19628084
DOI: Full-text: DOI:10.1016/j.surg.2009.05.005

BACKGROUND: 5-fluorouracil (5FU) is associated with significant GI side-effects. Randomized trials have shown a 50% reduction in severe diarrhea with chrono-chemotherapy versus conventional regimens at similar doses. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in 5FU breakdown. We hypothesized that DPD has a circadian expression pattern, accounting for the reduced GI side effects of chrono-modulated 5FU therapy. METHODS: Fifty-one rats were killed at 3-hourly intervals over 24 hours. DPD and thymidylate synthase (TS) mRNA in jejunal and colonic mucosa were measured using qRT-PCR. Cosinor analysis was used for statistical comparison. RESULTS: There was a significant circadian rhythm in the DPD mRNA expression in jejunum (1.7-fold, P < .001) and colon (1.5 fold, P < .01), with a peak expression in early sleep phase, and a trough at mid-wake cycle. TS also followed a circadian rhythm in jejunal mucosa with a peak at early rest phase. CONCLUSION: This rhythm in DPD expression may explain the benefit of chrono-chemotherapy. The peak of DPD expression in sleep phase in rats corresponds to time for lower GI adverse effects in chrono-chemotherapy in human trials. We believe better understanding of this process allows development of novel approaches to optimize the timing of chemotherapy without the administrative challenges of chronotherapy.


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RGD Object Information
RGD ID: 5133425
Created: 2011-06-16
Species: All species
Last Modified: 2011-06-16
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.