Effects of chronic jet lag on tumor progression in mice.

Frequent transmeridian flights or predominant work at night can increase cancer risk. Altered circadian rhythms also predict for poor survival in cancer patients, whereas physical destruction of the suprachiasmatic nuclei (SCN), the hypothalamic circadian pacemaker, accelerates tumor growth in mice. Here we tested the effect of functional disruption of circadian system on tumor progression in a novel experimental model of chronic jet lag. B6D2F(1) mice were synchronized with 12 hours of light and 12 hours of darkness or underwent repeat 8-hour advances of the light/dark cycle every 2 days before inoculation of Glasgow osteosarcoma. The 24-hour changes were assessed for plasma corticosterone, clock protein mPER1 expression in the SCN, and mRNA expression of clock genes mPer2 and mRev-erbalpha in liver and tumor. Time series were analyzed by spectral analysis and/or Cosinor. Differences were compared with analysis of variance (ANOVA). The 24-hour rest/activity cycle was ablated, and the rhythms of body temperature, serum corticosterone, and mPER1 protein expression in the SCN were markedly altered in jet-lagged mice as compared with controls (ANOVA, P < 0.001 for corticosterone and P = 0.01 for mPER1). Tumor grew faster in the jet-lagged animals as compared with controls (ANOVA, P < 0.001), whereas exposure to constant light or darkness had no effect (ANOVA, P = 0.66 and P = 0.8, respectively). The expression of mPer2 and mRev-erbalpha mRNAs in controls showed significant circadian rhythms in the liver (P = 0.006 and P = 0.003, respectively, Cosinor) and in the tumor (P = 0.04 and P < 0.001). Both rhythms were suppressed in the liver (P = 0.2 and P = 0.1, respectively, Cosinor) and in the tumor (P = 0.5) of jet-lagged mice. Altered environmental conditions can disrupt circadian clock molecular coordination in peripheral organs including tumors and play a significant role in malignant progression.

Circadian expression of dihydropyrimidine dehydrogenase, thymidylate synthase, c-myc and p53 mRNA in mouse liver tissue.

BACKGROUND & OBJECTIVE: Anti-cancer effect of 5-Fluorouracil (5-FU) is mediated mainly by inhibition of the thymidylate synthase (TS), while dihydropyrimidine dehydrogenase (DPD) is an initial and a rate-limiting catabolic enzyme of 5-FU. In this study, the mRNA expression profiles of TS, DPD, p53 and c-myc were investigated in mouse liver. METHODS: A total of 24 male B6D2F1 mice were involved in this study. All the mice were synchronized with an alternation of 12 h of light (L) and 12 h of darkness (D) (LD12:12) for 4 weeks. Body temperature and rest-activity were monitored with an intra-peritoneal sensor. All the mice were sacrificed at 3, 7, 11, 15, 19, 23 HALO (hours after light onset) respectively and liver samples were obtained and immediately frozen in liquid nitrogen. Total RNA was extracted from the frozen liver samples and one-step real-time quantitive RT-PCR was performed using LightCycler - RNA Amplification Kit SYBR Green I system. RESULTS: Both body temperature and rest-activity displayed similarly rhythmic patterns with peak times located in darkness, while the trough time was located in the light span. DPD showed a circadian expression in mRNA level with a peak at about 16 HALO (P=0.0012). TS showed a trend for a circadian rhythm, with a peak during light (P=0.079). Neither c-myc nor p53 displayed significant circadian rhythm. CONCLUSION: The 24-h patterns in DPD and TS expression were approximately 12 h out of phase, supporting a coordinated regulation of both transcriptional pathways relevant for 5-FU chronopharmacology.