[Rich66]

Summary
Chronobiology International
2002, Vol. 19, No. 1, Pages 1-19

Ann Pharm Fr. 2008 Jun;66(3):175-84.
[The circadian-timing system: a determinant of drug activity and a target of anticancer treatments]

[Article in French]
Lévi F.
Inserm, U776 rythmes biologiques et cancers, hôpital Paul-Brousse, université Paris-Sud-11, 94804 Villejuif, France. francis.levi@inserm.fr
Cellular proliferation and drug detoxification are controlled over the 24h by the circadian-timing system, whose disruption can favor malignant processes. Thus, prolonged shift work appears to increase the risk of breast, colon or prostate cancer. Alterations in circadian physiology and/or molecular-clock genes accelerate cancer progression in experimental models and in cancer patients. In addition, anticancer treatments can also dampen or reinforce the circadian-timing system, as a function of dose and time of administration. The adjustment of anticancer-drug delivery to the circadian-timing system (chronotherapeutics) has allowed to reduce five-fold the incidence of severe adverse events as compared to constant rate infusion or wrongly-timed chronomodulated delivery in cancer patients. In experimental models, the best antitumor efficacy is usually obtained following treatment delivery near the least toxic time, a statement that also seems to apply to patients. Dedicated technologies include programmable in time pumps and rhythm monitors and are required for chronotherapeutics. Recent results have revealed that the optimal chronotherapeutic schedule could differ as a function of gender and circadian physiology. In conclusion, the circadian-timing system was shown to negatively control malignant proliferation via partly identified molecular mechanisms. The components of the circadian-timing system thus constitute new potential therapeutic targets in oncology. Mathematical models help toward a better understanding of the role of variability for the determination of the optimal chronotherapeutic schedule and constitute useful tools for the personalization of cancer chronotherapeutics.

PMID: 18706346 [PubMed - indexed for MEDLINE]


From circadian rhythms to cancer chronotherapeutics
Francis Lévi* Université Paris XI, INSERM EPI 0118 “Cancer Chronotherapeutics,”

Mammalian circadian rhythms result from a complex organization involving molecular clocks within nearly all “normal” cells and a dedicated neuroanatomical system, which coordinates the so-called “peripheral oscillators.” The core of the central clock system is constituted by the suprachiasmatic nuclei that are located on the floor of the hypothalamus. Our understanding of the mechanisms of circadian rhythm generation and coordination processes has grown rapidly over the past few years. In parallel, we have learnt how to use the predictable changes in cellular metabolism or proliferation along the 24h time scale in order to improve treatment outcome for a variety of diseases, including cancer. The chronotherapeutics of malignant diseases has emerged as a result of a consistent development ranging from experimental, clinical, and technological prerequisites to multicenter clinical trials of chronomodulated delivery schedules. Indeed large dosing-time dependencies characterize the tolerability of anticancer agents in mice or rats, a better efficacy usually results from treatment administration near the least toxic circadian time in rodent tumor models. Programmable in time multichannel pumps have allowed to test the chronotherapy concepts in cancer patients and to implement chronomodulated delivery schedules in current practice. Clinical phase I and II trials have established the feasibility, the safety, and the activity of the chronotherapy schedules, so that this treatment method has undergone further evaluation in international multicenter phase III trials. Overall, more than 2000 patients with metastatic disease have been registered in chronotherapy trials. Improved tolerability and/or better antitumor activity have been demonstrated in randomized multicenter studies involving large patient cohorts. The relation between circadian rhythmicity and quality of life and even survival has also been a puzzling finding over the recent years. An essential step toward further developments of circadian-timed therapy has been the recent constitution of a Chronotherapy cooperative group within the European Organization for Research and Treatment of Cancer. This group now involves over 40 institutions in 12 countries. It is conducting currently six trials and preparing four new studies. The 19 contributions in this special issue reflect the current status and perspectives of the several components of cancer chronotherapeutics.
Full Text | PDF (338 KB) | PDF Plus (353 KB)


Earlier work specific to Vinorelbine referenced here:
http://jpet.aspetjournals.org/cgi/reprint/289/1/231.pdf

Relationship Between Circadian Rhythm of Vinorelbine Toxicity
and Efficacy in P388-Bearing Mice
ELISABETH FILIPSKI, SOPHIE AMAT, GUY LEMAIGRE, MARC VINCENTI, FABIENNE BREILLOUT, and
FRANCIS A. LÉVI2
Laboratoire “Rythmes Biologiques et Chronothe´ rapeutique,” Institut du Cancer et d’Immunoge´ ne´ tique, Hoˆ pital Paul Brousse, Villejuif, France
(E.F., S.A., G.L., F.L.); and Pierre Fabre Oncologie, Boulogne-Billancourt, France (M.V., F.B.)
Accepted for publication November 13, 1998 This paper is available online at http://www.jpet.org
ABSTRACT
The relevance of chronopharmacology for improving tolerability and antitumor efficacy of the antimitotic drug vinorelbine was investigated in female B6D2F1 mice standardized with 12 h of light and 12 h of darkness. A single i.v. vinorelbine dose (26mg/kg) was given to 279 mice at 7, 11, 19, or 23 hours after light
onset (HALO). Bone marrow necrosis and leukopenia were nearly twice as large in the mice injected at 7 HALO as compared with those treated at 19 HALO (ANOVA: p , .001 and p 50.004, respectively). The relevance of vinorelbine dosing time for antitumor efficacy was assessed in 672 P388 leukemia bearing mice. Vinorelbine was injected as a single dose (20, 24,26, or 30 mg/kg) or weekly (20, 24, 26, or 28 mg/kg/injection 33) at one of six circadian times, 4 h apart. A significant correlation between single dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened median survival time
in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/kg: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those treated at 19 HALO (20 mg/kg: 28.5 days; 24 mg/kg: 32 days; and 26 mg/kg: 36 days). The study demonstrates the circadian rhythm dependence of maximum tolerated dose and the need to deliver maximum tolerated dose at the least toxic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.





[Cancer Research 61, 1996-2001, March 1, 2001]
© 2001 American Association for Cancer Research

Experimental Chronotherapy of Mouse Mammary Adenocarcinoma MA13/C with Docetaxel and Doxorubicin as Single Agents and in Combination¹
LINK to full text and PDF
T. G. Granda, E. Filipski, R. M. D’Attino, P. Vrignaud, A. Anjo, M. C. Bissery and F. Lévi² Laboratoire Rythmes Biologiques et Chronothérapeutique (Université Paris XI, Institut du Cancer et d’Immunogénetique) [T. G. G., E. F., R. M. D., F. L.], and Service d’Anatomie Pathologique [A. A.], Hôpital Paul Brousse, 94800 Villejuif, France; Oncologia Medica Complementare, Regina Elena Institute, Rome, Italy [R. M. D.]; and Aventis Pharma S.A., Vitry sur Seine, France [P. V., M. C. B.]
The therapeutic index of docetaxel, doxorubicin and their combination may be improved by an adequate selection of the circadian time of administration. The present study constitutes a prerequisite to testing the clinical relevance of chronotherapy in human breast cancer. Three experiments were performed in C3H/HeN mice. Each treatment modality was administered i.v. once a week for 3 weeks at one of six circadian stages, during the light span, when the mice were resting: 3, 7, and 11 h after light onset (HALO), or during darkness, when the mice were active: 15, 19, and 23 HALO. The circadian time dependency of single agent tolerability was investigated in healthy mice using four dose levels for docetaxel (38.8, 23.3, 14, and 8.4 mg/kg/injection) and for doxorubicin (13.8, 8.3, 5 and 3 mg/kg/injection; experiment 1). The circadian time dependency of each single agent efficacy was studied in MA13/C-bearing mice, using two dose levels of docetaxel (38.8 or 23.3 mg/kg/injection) or doxorubicin (8.3 or 5 mg/kg/injection; experiment 2). The toxicity and the efficacy of the simultaneous docetaxel-doxorubicin combination were assessed as a function of dosing time in experiment 3. Two combinations were tested (A, 16.3 mg/kg/injection of docetaxel and 2.5 mg/kg/injection of doxorubicin; and B, 11.6 and 3.5 mg/kg/injection, respectively) at each of the above six circadian times. Mortality, body weight change, and tumor size were recorded for 60–70 days in each experiment. Single agent docetaxel or doxorubicin was significantly best tolerated near the middle of the rest span (7 HALO) and most toxic in the middle of the activity phase (19 HALO). Docetaxel or doxorubicin as a single drug were also most effective at 7 HALO, irrespective of dose. Treatment at 7 HALO produced highest rates of complete tumor inhibition (81% versus 11% at 3 HALO for docetaxel, p from ² <0.001, and 69% versus 44% at 11 HALO for doxorubicin, not significant) and highest day 60 survival rate (100% versus 28% at 3 HALO for docetaxel, p from ² <0.001 and 89% versus 69% at 15 HALO for doxorubicin, not significant). Docetaxel-doxorubicin combinations were most effective following dosing in the beginning of the rest span or short after the onset of the activity span, with regard to the rates of both complete tumor inhibitions (45% at 3 HALO versus 15% at 19 HALO) and day 70 survival rates (85% and 80% at 3 and 7 HALO respectively, versus 20% at 19 HALO). The efficacy of single agent docetaxel or doxorubicin and that of their combination varied largely as a function of circadian dosing time. Single agent docetaxel at 7 HALO was the best treatment option in this model with regard to both tolerability and efficacy. This timing may correspond to the middle of the night in cancer patients.

The rate of complete tumor inhibitions displayed large variations as a function of both dose and dosing time for each single drug. Indeed, each dose level of docetaxel was more than 5-fold as active at 7 HALO as at 3 HALO. A similar difference was found for the nontoxic dose of doxorubicin, with 7 HALO being also the most effective dosing time.

Despite the overall rate of complete tumor inhibitions was larger with combination A than with combination B (45 and 20%, respectively), the overall efficacy of docetaxel-doxorubicin was lower than that achieved with the highest dose tested for each single agent (docetaxel, 58%; doxorubicin, 96%).
The tolerability of the most effective combination (A) was worse than that of single agent docetaxel (23.3 mg/kg/injection). Yet both the rate of complete tumor inhibition (42% versus 45%) and that of survival on day 60 (70% versus 75%) were similar. Single agent doxorubicin (5 mg/kg/injection) was better tolerated but less effective than combination A (45% versus 15% of complete regressions). Nevertheless, the survival rates on day 60 were similar (75% and 62%). Thus, the most active combination did not improve the survival outcome of mice as compared with docetaxel or doxorubicin given as single agents at a nontoxic dose.

In conclusion, the circadian dosing time of single agent docetaxel or doxorubicin or their combination profoundly influenced tolerability and antitumor efficacy in mice with MA13/C mammary adenocarcinoma. Each single agent produced the best results after administration near the middle of the rest span. Furthermore, single agent delivery at its optimal dosing time displayed better tolerability and efficacy than both tested docetaxel-doxorubicin combinations. Although these results do not rule out a favorable therapeutic index of other drug sequences or intervals in this model, they support the investigation of the clinical relevance of chronotherapy of human breast cancer. The therapeutic index of single agent docetaxel or doxorubicin would be expected to be improved after their administration at night in cancer patients