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. 2001 May;92(5):554-61.
doi: 10.1111/j.1349-7006.2001.tb01129.x.

CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver

M Shimizu  1 , T Tamura, Y Yamada, Y Akiyama, N Saijo, K Nishio
Affiliations

CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver

M Shimizu et al. Jpn J Cancer Res. 2001 May.

Abstract

Combination chemotherapy consisting of 5-fluorouracil (5-FU) and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carboxycamptothecin (CPT-11) is a promising regimen for gastrointestinal cancer. The circadian-dependent efficacy and toxicity of 5-FU are related to the circadian variation in the activity of dihydropyrimidine dehydrogenase (DPD), which is a rate-limiting enzyme in the pyrimidine catabolic pathway. To optimize the schedule of the CPT-11 plus 5-FU combination, we investigated the effect of CPT-11 on the circadian rhythm of DPD in vivo. In control mice, the DPD mRNA level in the liver was significantly higher at 14:00 than that at 02:00. After intravenous administration of CPT-11 (30 mg / kg) at 20:00, the circadian rhythm of the DPD mRNA level in the liver was no longer observed 18 h later (14:00), but it was unaffected 6 and 18 h later (at 14:00 and 02:00) when CPT-11 was given at 08:00. In addition, a dose-dependent lengthening of the period of the circadian rhythm of DPD was observed for 42 h after intravenous injection of CPT-11 at 20:00. The levels of DPD protein and activity at 21 h after administration of CPT-11 (at 17:00) were significantly higher than at 9 h (at 05:00). These results suggest that CPT-11 may influence the circadian rhythm of DPD at the transcriptional level. Modulation of the circadian rhythm of DPD by CPT-11 may be a factor in optimizing the combination of 5-FU and CPT-11.

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