Annual Review of Pharmacology and Toxicology
Vol. 50 (Volume publication date February 2010)
Circadian Timing in Cancer Treatment
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Abstract
Annual Review of Pharmacology and Toxicology
Vol. 50 (Volume publication date
February 2010)
Review in Advance first posted online on November 17, 2009. (Changes may still occur before final publication online and in print.)Circadian Timing in Cancer Treatments
Francis Lévi
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, F-94807, France; Univ Paris-Sud, UMR-S0776, Orsay, F-91405, France; Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif, F-94807, France; email:
francis.levi@inserm.fr
Alper Okyar
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, F-94807, France and Istanbul University Faculty of Pharmacy, Department of Pharmacology, Beyazit TR-34116, Istanbul, Turkey; email:
aokyar@istanbul.edu.tr
Sandrine Dulong
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, F-94807, France; Univ Paris-Sud, UMR-S0776, Orsay, F-91405, France; email:
sandrine.dulong@inserm.fr
Pasquale F. Innominato
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, F-94807, France; Univ Paris-Sud, UMR-S0776, Orsay, F-91405, France; Assistance Publique-Hôpitaux de Paris, Unité de Chronothérapie, Département de Cancérologie, Hôpital Paul Brousse, Villejuif, F-94807, France; email:
sandrine.dulong@inserm.fr
Jean Clairambault
INSERM, U776 Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, F-94807, France; Univ Paris-Sud, UMR-S0776, Orsay, F-91405, France; and INRIA Rocquencourt, Domaine de Voluceau, BP 105, F78153 Rocquencourt, France; email:
jean.clairambault@inserm.fr
The circadian timing system is composed of molecular clocks which drive 24-h changes in xenobiotic metabolism and detoxification, cell cycle events, DNA repair, apoptosis, and angiogenesis. The cellular circadian clocks are coordinated by endogenous physiological rhythms, so that they tick in synchrony in the host tissues that can be damaged by anticancer agents. As a result, circadian timing can modify 2- to 10-fold the tolerability of anticancer medications in experimental models and in cancer patients. Improved efficacy is also seen when drugs are given near their respective times of best tolerability, due to (a) inherently poor circadian entrainment of tumors and (b) persistent circadian entrainment of healthy tissues. Conversely, host clocks are disrupted whenever anticancer drugs are administered at their most toxic time. On the other hand, circadian disruption accelerates experimental and clinical cancer processes. Gender, circadian physiology, clock genes, and cell cycle critically affect outcome on cancer chronotherapeutics. Mathematical and systems biology approaches currently develop and integrate theoretical, experimental, and technological tools in order to further optimize and personalize the circadian administration of cancer treatments.
Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 50 is January 06, 2010. Please see
http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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PLoS Comput Biol. 2010 Mar 19;6(3):e1000712.
Tumor growth rate determines the timing of optimal chronomodulated treatment schedules.
PDF download
Bernard S,
Cajavec Bernard B,
Lévi F,
Herzel H.
Institute for Theoretical Biology, Humboldt University and Charité, Berlin, Germany.
In host and cancer tissues, drug metabolism and susceptibility to drugs vary in a circadian (24 h) manner. In particular, the efficacy of a cell cycle specific (CCS) cytotoxic agent is affected by the daily modulation of cell cycle activity in the target tissues. Anti-cancer chronotherapy, in which treatments are administered at a particular time each day, aims at exploiting these biological rhythms to reduce toxicity and improve efficacy of the treatment. The circadian status, which is the timing of physiological and behavioral activity relative to daily environmental cues, largely determines the best timing of treatments. However, the influence of variations in tumor kinetics has not been considered in determining appropriate treatment schedules. We used a simple model for cell populations under chronomodulated treatment to identify which biological parameters are important for the successful design of a chronotherapy strategy.
We show that the duration of the phase of the cell cycle targeted by the treatment and the cell proliferation rate are crucial in determining the best times to administer CCS drugs. Thus, optimal treatment times depend not only on the circadian status of the patient but also on the cell cycle kinetics of the tumor. Then, we developed a theoretical analysis of treatment outcome (TATO) to relate the circadian status and cell cycle kinetic parameters to the treatment outcomes. We show that the best and the worst CCS drug administration schedules are those with 24 h intervals, implying that
24 h chronomodulated treatments can be ineffective or even harmful if administered at wrong circadian times. We show that for certain tumors, administration times at intervals different from 24 h may reduce these risks without compromising overall efficacy.
PMID: 20333244 [PubMed - in process]
Quote:
Author Summary
Chronotherapy of cancers aims at exploiting daily physiological rhythms to improve anti-cancer efficacy and
tolerance to drugs by administering treatments at a specific time of the day. Recent clinical trials have shown
that chronotherapy can be beneficial in improving quality of life and median life span in patients, but that it can also
have negative effects if the timing is wrong. A theoretical basis for the rational development of individualized
therapy schedules is still lacking. Here, we use a simple cell population model to show how biological rhythms
and the cell cycle interact to modulate the response to cancer therapy. In particular, we show that the proliferation
rate of cancer cells determines when treatments are most effective. We provide a simple formulation of the
problem that can be used to compute an objective response function based on the drug sensitivity and the
proliferation rate of tumor cells. Finally, we show that in some cases, treating at a different time every day may be
more appropriate than standard daily chronotherapy.
These results constitute an important step in designing individualized chronotherapy treatments, and point out to
ways to design better clinical trials.
|
Cancer Res. 2006 Nov 15;66(22):10720-8.
Improved tumor control through circadian clock induction by Seliciclib (Roscovatine), a cyclin-dependent kinase inhibitor.
Iurisci I,
Filipski E,
Reinhardt J,
Bach S,
Gianella-Borradori A,
Iacobelli S,
Meijer L,
Lévi F.
Institut National de la Santé et de la Recherche Médicale, U776 "Rythmes Biologiques et Cancers," Hôpital Paul Brousse, Villejuif Cedex, France.
The circadian timing system and the cell division cycle are frequently deregulated in cancer. The therapeutic relevance of the reciprocal interactions between both biological rhythms was investigated using Seliciclib, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Mice bearing Glasgow osteosarcoma received Seliciclib (300 mg/kg/d orally) or vehicle for 5 days at Zeitgeber time (ZT) 3, 11, or 19. On day 6, tumor mRNA 24-hour expression patterns were determined for clock genes (Per2, Rev-erbalpha, and Bmal1) and clock-controlled cell cycle genes (c-Myc, Wee1, cyclin B1, and CDK1) with quantitative reverse transcription-PCR. Affinity chromatography on immobilized Seliciclib identified CDK1/CDK2 and extracellular signal-regulated kinase (ERK) 1/ERK2, CDK7/CDK9, and casein kinase CK1epsilon as Seliciclib targets, which respectively regulate cell cycle, transcription, and circadian clock in Glasgow osteosarcoma.
Seliciclib reduced tumor growth by 55% following dosing at ZT3 or ZT11 and by 35% at ZT19 compared with controls (P < 0.001). Tolerability was also best at ZT3. Mean transcriptional activity of Rev-erbalpha, Per2, and Bmal1 was arrhythmic in the tumors of untreated mice.
Seliciclib induced rhythmic clock gene expression patterns with physiologic phase relations only after ZT3 dosing. c-Myc and Wee1 mRNAs displayed synchronous circadian rhythms in the tumors of control mice receiving vehicle only but not in those of mice given the drug. Seliciclib further enhanced Wee1 expression irrespective of dosing time, an effect that reinforced G(2)-M gating. Seliciclib also inhibited CK1epsilon, which determines circadian period length.
The coordination of clock gene expression patterns in tumor cells was associated with best antitumor activity of Seliciclib. The circadian clock and its upstream regulators represent relevant targets for CDKIs.
PMID: 17108108 [PubMed - indexed for MEDLINE]
Chronobiol Int. 2009 Aug;26(6):1169-88.
Liver circadian clock, a pharmacologic target of cyclin-dependent kinase inhibitor seliciclib (Roscovatine).
Iurisci I,
Filipski E,
Sallam H,
Harper F,
Guettier C,
Maire I,
Hassan M,
Iacobelli S,
Lévi F.
INSERM, U 776 Rythmes biologiques et cancers, Hôp. P. Brousse, Villejuif, F-94807, France.
Circadian disruption accelerates malignant growth and shortens survival, both in experimental tumor models and cancer patients. In previous experiments, tumor circadian disruption was rescued with seliciclib, an inhibitor of cyclin-dependent kinases (CDKs). This effect occurred at a selective dosing time and was associated with improved antitumor activity. In the current study, seliciclib altered robust circadian mRNA expression of the clock genes Rev-erb alpha, Per2, and Bmal1 in mouse liver following dosing at zeitgeber time (ZT) 3 (i.e., 3 h after the onset of the 12 h light span), when mice start to rest, but not at ZT19, near the middle of the 12 h dark span, when mice are most active. However, liver exposure to seliciclib, as estimated by the liver area under the concentration x time curve (AUC), was approximately 80% higher at ZT19 than at ZT3 (p = 0.049). Circadian clock disruption was associated with increased serum liver enzymes and modified glycogen distribution in hepatocytes, as revealed by biochemical determinations and optic and electronic microscopy. The extent of increase in liver enzymes was most pronounced following dosing at ZT3, as compared to ZT19 (p < 0.04). Seliciclib further up-regulated the transcriptional activity of c-Myc, a cell cycle gene that promotes cell cycle entry and G1-S transition (p < 0.001), and down-regulated that of Wee1, which gates cell cycle transition from G2 to M (p < 0.001). These effects did not depend upon drug dosing time. Overall, the
results suggest the circadian time of seliciclib delivery is more critical than the amount of drug exposure in determining its effects on the circadian clock. Seliciclib-induced disruption of the liver molecular clock could account for liver toxicity through the resulting disruption of clock-controlled detoxification pathways. Modifications of cell cycle gene expression in the liver likely involve other mechanisms. Circadian clocks represent relevant targets to consider for optimization of therapeutic schedules of CDK inhibitors.
PMID: 19731111 [PubMed - indexed for MEDLINE]
Adv Drug Deliv Rev. 2007 Aug 31;59(9-10):1015-35. Epub 2007 Jul 4.
Implications of circadian clocks for the rhythmic delivery of cancer therapeutics.
Lévi F,
Focan C,
Karaboué A,
de la Valette V,
Focan-Henrard D,
Baron B,
Kreutz F,
Giacchetti S.
INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, Villejuif, F-94807, France.
levi-f@vjf.inserm.fr
The
circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell,
circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates
circadian rhythms. As a result, both
the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in-time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to
circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer.
The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin.
Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where
sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient.
Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics.
PMID: 17692427 [PubMed - indexed for MEDLINE]
Timing Chemotherapy (2005)
http://www.sciencentral.com/articles...392615&cat=1_3
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| For people with cancer, chemotherapy can be nearly as bad as the cancer. But, as this ScienCentral News video reports, some doctors and scientists think it may be possible to make treatments easier by using our bodies' own biological clocks.
It's All In The Timing
George Martin knows there is nothing to look forward to about chemotherapy. He's 67, has prostate cancer, and would rather spend his time grooming his lawn or fishing, than watch anti-cancer drugs flow into his arm. He's even less thrilled about the potential side effects.
"I hope I don't have to go through that chemotherapy, but if so, so be it," he says in a South Carolina accent.
But Martin is lucky. If a time comes when he needs chemotherapy, his doctors plan on using a rare drug delivery technique known as chronotherapy. Chronotherapy is the timing of the delivery of any type of treatment (including chemotherapy, radiation, or even surgery) based on a patient's internal biological clock or circadian rhythm.
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