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


CONCLUSIONS
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.
Abolmaali
Kamran
K
Department of Surgery, Brigham and Women's Hospital, Boston, MA; Harvard Medical School, Boston, MA 02115, USA.
Balakrishnan
Anita
A
Stearns
Adam T
AT
Rounds
Jan
J
Rhoads
David B
DB
Ashley
Stanley W
SW
Tavakkolizadeh
Ali
A
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002940:Circadian Rhythm; D003106:Colon / Q000201:enzymology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism*; D055870:Drug Chronotherapy; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000201:enzymology*; D007583:Jejunum / Q000201:enzymology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013940:Thymidylate Synthase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil