[Circadian variations of dihydropyrimidine dehydrogenase (DPD) activity in oral mucosa of healthy volunteers]. / Etude des variations circadiennes de l'activité de la dihydropyrimidine déshydrogénase (DPD) dans la muqueuse buccale chez des sujets volontaires sains.

UNLABELLED: Dihydropyrimidine dehydrogenase (DPD) is the rate limiting enzyme of 5-fluoro-uracil (5-FU) catabolism. DPD rhythmicity, peak at 1:00 is an important determinant of 5-FU tolerability and has practical implications for the pattern of chronomodulated delivery of the drug. Maximal tolerated doses have been highed and anti-tumour activity also. But 30% patients have toxicities expressed by mucositis in oral mucosa. PURPOSE: Titrate DPD activity in oral mucosa in healthy subjects, in oral mucosa which is the target of 5-FU, at 10:00 and midnight could help to understand toxicities in patients. SUBJECTS AND METHODS: Eight healthy subjects participated (information note signed by patients). One oral mucosa sample was drawn at 10:00 and an other at midnight. DPD activity was analyzed by a H.P.L.C. method. RESULTS: DPD activity in oral mucosa varied from 0.004 to 0.13 nmol x min(-1) x mg(-1) prot at 10:00 and from 0.07 to 0.16 nmol x min(-1) x mg(-1) prot at midnight, with a 30% average relative increase from morning to midnight (range: -20% to +100%; statistical significant difference with P <0.073). CONCLUSION: DPD circadian changes in healthy oral mucosa subjects remained to agree to mononuclear cell, with increase at midnight.

Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status.

The rest/activity circadian cycle has been used as a reference for chemotherapy administration at specific times to improve tolerability and efficacy. Because cancer processes may be associated with alterations of circadian rhythms, the rest/activity cycle was monitored noninvasively to assess its relationship with tumor response, survival, and quality of life in 200 patients with metastatic colorectal cancer. Patients wore an actigraph, a wristwatch that records the number of accelerations per minute, for 3 days before receiving chronomodulated chemotherapy. The circadian rhythms in activity were estimated by two robust parameters: the autocorrelation coefficient at 24 h (r24), and the dichotomy index (I

Non-invasive estimation of the circadian rhythm in serum cortisol in patients with ovarian or colorectal cancer.

The variability in toxicity or efficacy of cancer chronotherapy among patients may be due to differences in circadian rhythm. Adequate assessment of circadian rhythm often requires repeated blood sampling over at least a 24-hr period; this cannot be a routine procedure. We attempted to assess the reliability of a 2-timepoint estimate of the 24-hr rhythm of serum cortisol in 19 healthy subjects, 19 women with ovarian cancer and 18 patients with metastatic colorectal cancer. The difference between daily maximum and minimum values (MAX-MIN) was compared with that observed between values at 08.00 and at 16.00 (H8-H16). As significant correlations were found between both variables in all groups, we conclude that the magnitude of circadian changes in serum cortisol may be estimated from blood samples collected at 08.00 and at 16.00. The clinical relevance and the prognostic value of this method of assessment are currently under evaluation in a larger-scale clinical trial.

Circadian-system alterations during cancer processes: a review.

Murine and human data have indicated that tumors and tumor-bearing hosts may exhibit nearly normal or markedly altered circadian rhythms. Amplitude damping, phase shifts, and/or period (tau) change, including appearance of ultradian rhythms (with tau < 20 hr) usually become more prominent at late stages of cancer development. The extent of rhythm alterations also varies according to tumor type, growth rate and level of differentiation. While "group chronotherapy," i.e., administration of the same chronomodulated schedule to cancer patients, has increased chemotherapy efficacy and/or tolerability, cancer patients' individual circadian rhythms now need to be explored on a large scale, in order to estimate the incidence of cancer-associated circadian-system alterations and to understand the underlying mechanisms. Correlations between such alterations and patient outcome must be established in order to specify the need for individualized chronomodulated delivery schedules and/or specific rhythm-oriented therapy, especially in patients with circadian-system disturbances.

[Study of circadian rhythms of activity by actometry: preliminary results in 30 patients with metastatic colorectal cancer]. / Etude des rythmes circadiens d'activité par actométrie: résultats préliminaires chez 30 patients atteints de cancer colorectal métastasé.

Activity circadian rhythms were measured non-invasively in 30 patients with metastatic colorectal cancer by wrist actigraphy, and compared with control data. Patients and control subjects were requested to wear the actigraph at home for 2 to 5 days. Control time-series exhibit high activity levels (150 to 350 counts/min) during daytime, followed by low activity levels (0 to 50 counts/min) during the night. In patients, the contrast between daytime activity and nocturnal sleep is noticeably less marked, and a wide inter-patient variability can be observed. This alteration of the rest-activity rhythm in the cancer group was statistically validated by autocorrelation test. Results from the cosinor and he maximal entropy spectral analysis must be interpreted more cautiously, since the prerequisites for these tests may not be fulfilled by actometric time-series. These results indicate that cancer patients may have altered rest-activity circadian rhythms. The significance and prognostic value of such alterations deserve further testing in a larger population. Actigraphy may provide a simple and innovative tool to study the circadian system in cancer patients.

Circadian rhythm and seasonal dependence in the toxicological response of mice to epirubicin.

Compared to doxorubicin, equimolar epirubicin toxicity is reduced by about 50% by the epimerization of a hydrogen and hydroxyl group at the 4' position of the anthracycline sugar moiety. The circadian timing of doxorubicin administration markedly affects its lethal and sub-lethal bone marrow and gut toxicities in mice, as well as the severity of its clinical toxicity. We tested whether the timing of administration of equitoxic epirubicin doses similarly affected the toxicological response in female CD2F1 mice. A large and highly reproducible effect of the circadian stage of administration was documented with best drug tolerance occurring during the first half of the daily rest (light) span of the animals. In addition to this circadian rhythm, a significant seasonal effect was found with significantly fewer deaths occurring after epirubicin was given in the Summer, as compared to the Winter. Safest circadian timing for epirubicin is statistically significantly earlier in the day than for doxorubicin, while their seasonal patterns are quite similar.

Circadian synchronization of hepatocyte proliferation in young rats: the role played by adrenal hormones.

The circadian rhythm of hepatic cell proliferation in rats appears on the 20th day of life, when the hypothalamo-adrenal axis is mature enough for circadian activity to occur. From the 20th day to the 30th day of life, the mitotic rhythm is progressively induced by a reduction in nocturnal values, while diurnal rhythms remain unchanged. Mitotic peaks emerge at 10.00 hours. A labelling index wave occurs 8 hr before the corresponding mitotic wave, with a peak at 02.00 hours and a minimum in the evening, coincidental with the acrophase of plasma corticosterone level (activity phase). Labelled mitoses curves and metaphase accumulation after colchicine injection show that the duration of the S, G2 and M phases remain approximately constant and that the circadian variation is due to a variation in the rate of cells that enter these successive phases. During the synchronization period (from day 20 to 30), the growth fraction decreases progressively. Adrenalectomy at this time is followed by a higher cell proliferation and all rhythms disappear after 2 days. Corticosterone injected before the triggering of the rhythmic activity in 17-day-old rats immediately reduces the labelling index, while the mitotic index is decreased 10 hr later; this delay is equal to the S + G2 duration. The results are discussed. They favour the hypothesis that the circadian variation of corticosterone is responsible for the induction of a circadian variation in developmental cell proliferation by inhibition of the G1-S transition when it is higher in the evening.