Circadian Rhythm, eating schedule etc and treatment
Breast cancer chemotherapy disrupts sleep
Published: Sept. 1, 2009 at 3:57 PM
Repeated chemotherapy treatments can result in progressively worse and more enduring sleep-wake activity rhythms impairments, U.S. researchers said.
Principal investigator Sonia Ancoli-Israel of the University of California San Diego said the findings were not surprising because sleep disturbances are common in cancer patients and 30 percent to 50 percent report insomnia symptoms.
Although most variables returned to baseline levels in the second and third weeks of the first cycle of chemotherapy, circadian -- 24-hour cycles -- impairments were maintained.
"Results of this study suggest that our biological clocks are affected by chemotherapy," Ancoli-Israel said in a statement.
"Our biological clock, or circadian rhythm help keep our bodies in sync with the environment."
During chemotherapy, the biological clock gets out of sync, especially after the first cycle of treatment, but the clock seems to regulate itself after only one cycle. However, with repeated administration of chemotherapy, it becomes more difficult for the biological clock to readjust," the study said.
The finding is published in the journal Sleep.
n Vivo. 2010 Jul-Aug;24(4):471-87.A possible mechanism for altered immune response in the elderly.
BACKGROUND: Reciprocal influences and bidirectional connections among the nervous, endocrine and immune systems, mediated by shared neuroendocrine hormones, chemo/cytokines and binding sites contribute to the maintainment of body homeostasis. The hypothalamus-pituitary axis may play an immunomodulating role and influence cellular immune responses by releasing various hormones and neuropeptides into the blood with direct modulatory action on the immune effectors, or by regulating the hormonal secretion of peripheral endocrine glands. Aging is associated with changes in immune function. The aim of this study was to evaluate circadian variations of some endocrine and immune factors in the elderly.
MATERIALS AND METHODS: Serum levels of cortisol, melatonin, thyrotropin-releasing hormone (TRH), thyroid stimulating hormone (TSH), free thyroxine (FT(4)), growth hormone (GH), insulin-like growth factor (IGF) 1 and interleukin (IL) 2 were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from ten healthy young and middle-aged individuals (age 35-54 years) and from ten healthy elderly individuals (age 65-76 years).
RESULTS: There was a statistically significant difference between the groups in the observed values of CD20 and TSH serum levels (higher in the young and middle-aged) and CD25 and DR(+) T-cells (higher in the elderly). In the group of young and middle aged subjects, a clear circadian rhythm was validated for the time-qualified changes of all the factors studied, with the exception of FT(4), IGF1 and IL2. In the group of elderly individuals, a number of rhythms and correlations with neuroendocrine hormones were absent or altered.
CONCLUSION: The results of the current study evidence aging-associated decrease of peripheral B-cell compartment, increase of activated T-cell compartment, decrease of hypophyseal thyrotropin secretion, altered circadian rhythmicity and altered hormone-immune cell correlations.
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
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.
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.
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.
Re: Circadian Rhythm, eating schedule etc and treatment
Int J Colorectal Dis. 2010 Mar;25(3):343-50. Chronomodulated chemotherapy versus conventional chemotherapy for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.
Liao C, Li J, Bin Q, Cao Y, Gao F.
Department of Coloproctological Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.
PURPOSE: The purpose of this study was to systematically compare the efficacy and safety of chronomodulated chemotherapy with conventional chemotherapy in patients with advanced colorectal cancer. METHOD: Eligible studies were identified from electronic databases (Medline, Embase, and the Cochrane Library). The efficacy data included overall survival (OS) and objective response rate (ORR), and toxicities data contained diarrhea, vomiting and nausea, mucositis, asthenia, and peripheral sensory neuropathy. The meta-analysis was performed with the fixed-effect model or random-effect model according to heterogeneity. RESULT: From 79 articles screened, five randomized controlled trials (RCTs) met the inclusion criteria contributing a total of 958 participants. There was a significant OS benefit (hazard ratio (HR)=0.82; 95% confidence interval (CI) 0.69 to 0.97; P=0.023) in favor of the chronomodulated chemotherapy. The ORR was not significantly different between two arms (relative risk=1.27; 95% CI 0.88 to 1.83; P=0.196). A higher incidence of grade 3/4 mucositis (odds ratio=2.26, 95% CI 1.34 to 3.83; P=0.724), asthenia (2.15, 1.30 to 3.56; P=0.428), and a lower incidence of grade 3/4 neutropenia (0.26, 0.16 to 0.42; P=0.641) were associated with the chronomodulated chemotherapy. The two arms were similar in terms of grade 3/4 diarrhea (1.10, 0.72 to 1.69; P=0.756), vomiting and nausea (0.69, 0.42 to1.13; P=0.239), and peripheral sensory neuropathy (0.56, 0.25 to 1.27, 0.164). CONCLUSION: Chronomodulated chemotherapy showed significant improvement in OS comparing with conventional chemotherapy. Side effects of the chronomodulated chemotherapy are predictable and manageable. But these results still need more high-quality RCTs for confirmation.
PMID: 19936767 [PubMed - in process]
Cell Cycle. 2009 Jun 1;8(11):1665-7. Epub 2009 Jun 9. Circadian regulation of DNA excision repair: implications for chrono-chemotherapy.
Kang TH, Sancar A.
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
The mammalian circadian system synchronizes organisms' daily cyclical physiology from gene expression to gross behavioral patterns. A new study from our group suggests that DNA repair is also intimately linked to circadian rhythm. Since the repair of DNA lesions contributes to the resistance of chemotherapy with DNA damaging agents such as cisplatin, understanding the fundamental molecular mechanism regulating DNA repair pathways is important for cancer therapy. Here we review the significance of the connection linking the circadian clock with nucleotide excision repair and discuss potential implications for chemotherapy.
PMID: 19411851 [PubMed - indexed for MEDLINE]
http://www.sciencedaily.com/releases...113090501.htm# Chemotherapy Most Effective At Time Of Day When Particular Enzyme At Lowest Level ScienceDaily (Jan. 16, 2009) — For years, research has hinted that the time of day that cancer patients receive chemotherapy can impact their chances of survival. But the lack of a clear scientific explanation for this finding has kept clinicians from considering timing as a factor in treatment. Now, a new study from the University of North Carolina at Chapel Hill has suggested that treatment is most effective at certain times of day because that is when a particular enzyme system – one that can reverse the actions of chemotherapeutic drugs – is at its lowest levels in the body.
The study, performed in mice, could also have implications for the prevention of new cancers.
The enzyme system implicated – called nucleotide excision repair– repairs many types of DNA damage that come not just from chemotherapy but also from the ultraviolet rays of the sun. Thus, by understanding the cyclical nature of this system, physicians may be able to pinpoint when it is most crucial for people to protect themselves from sun exposure to minimize their risk of skin cancer.
"Timing is everything, and here we have molecular data showing why this is especially true with regard to cancer," said senior study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger Comprehensive Cancer Center and Sarah Graham Kenan professor of biochemistry and biophysics in the UNC School of Medicine. Sancar is also a member of the National Academy of Sciences and the Turkish Academy of Sciences. "By hitting cancer cells with chemo at a time when their ability to repair themselves is minimal, you should be able to maximize effectiveness and minimize side effects of treatment."
The study, published in the Proceedings of the National Academy of Sciences, provides the first solid evidence that the daily oscillations of the cell's repair machinery can affect the potency of cancer drugs.
The primary driver of this oscillatory behavior is the circadian clock, which keeps the biochemical, behavioral and physiological processes of many organisms, including mice and humans, on a 24-hour cycle. Every single cell in the body – whether from the kidney, liver or heart – has its own internal clock, and each of these are synchronized and coordinated by one master clock, located in a particular cluster of neurons in the brain.
Because of the important role that the circadian clock plays in regulating the daily rhythms of life, Sancar wanted to see what influence it had on important functions in the body, in particular the repair of damage to DNA caused by chemotherapy or UV radiation. This damage is usually repaired by a process called nucleotide excision repair, which cuts out and replaces sections of damaged DNA. Sancar and his colleagues studied the behavior of the repair machinery in cerebrum or brain tissue of mice over the course of a day, and found that the ability to repair damage was at a minimum in the early morning and reached a maximum in the evening hours. They then looked at each of the six components that make up the repair machinery and found that the levels of one of them – the enzyme XPA – rose and fell in synchrony with the oscillations of the circadian clock. Thus, the researchers demonstrated that the cell's ability to repair damage is linked to the circadian clock, and that this daily oscillation is ultimately due to changes in the levels of one particular enzyme at different times of day.
Sancar now wants to extend these studies to determine whether the same cyclical changes in repair activity seen in mouse brain can also be observed in mouse testis. This avenue is particularly relevant because cisplatin – a chemotherapeutic agent commonly used to treat testicular cancer – kills cancer cells by damaging DNA.
While cisplatin is considered by many people to be a miracle drug – it completely cured Lance Armstrong – one in ten patients who take it still do not survive and it is not as effective on other cancers, such as colon, ovarian and lung cancers. Sancar said he believes that identifying the times when the cancer cells' ability to repair damage is at a minimum may enable clinicians to tailor treatment and improve the survival rate for people with testicular cancer and these other more common cancers as well.
He also would like to see his findings being used for cancer prevention. Because the enzyme Sancar identified also repairs damage caused by sunlight, he plans to determine if the repair capacity in human skin changes as a function of the time of day.
"If we show the same patterns in humans as we did in mice, then it could tell us when would be the safest time to be in the sun (2 p.m. to 6 p.m.), and when would be the best time to avoid sun exposure (6 a.m. to 10 a.m.)," Sancar said. "The new information could help us prevent skin cancers."
The research was supported by the National Institutes of Health. Study co-authors from UNC department of biochemistry and biophysics include the lead author and postdoctoral scientist Tae-Hong Kang, Ph.D.; senior research associate Joyce T. Reardon; and postdoctoral scientist, Michael Kemp, Ph.D.
Reading between the lines, the suggestion here seems to be that chemo may be best received between 6 and 10am. Others have suggested this varies according to drugs used, individual adherence to circadian cycles and meal timing..
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)
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.
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 combinationmay be improved by an adequate selection of the circadian timeof administration. The present study constitutes a prerequisiteto testing the clinical relevance of chronotherapy in humanbreast cancer. Three experiments were performed in C3H/HeN mice.Each treatment modality was administered i.v. once a week for3 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 tolerabilitywas investigated in healthy mice using four dose levels fordocetaxel (38.8, 23.3, 14, and 8.4 mg/kg/injection) and fordoxorubicin (13.8, 8.3, 5 and 3 mg/kg/injection; experiment1). The circadian time dependency of each single agent efficacywas studied in MA13/C-bearing mice, using two dose levels ofdocetaxel (38.8 or 23.3 mg/kg/injection) or doxorubicin (8.3or 5 mg/kg/injection; experiment 2). The toxicity and the efficacyof the simultaneous docetaxel-doxorubicin combination were assessedas a function of dosing time in experiment 3. Two combinationswere tested (A, 16.3 mg/kg/injection of docetaxel and 2.5 mg/kg/injectionof doxorubicin; and B, 11.6 and 3.5 mg/kg/injection, respectively)at each of the above six circadian times. Mortality, body weightchange, and tumor size were recorded for 60–70 days ineach experiment. Single agent docetaxel or doxorubicin was significantlybest tolerated near the middle of the rest span (7 HALO) andmost toxic in the middle of the activity phase (19 HALO). Docetaxelor doxorubicin as a single drug were also most effective at7 HALO, irrespective of dose. Treatment at 7 HALO produced highestrates of complete tumor inhibition (81% versus 11% at 3 HALOfor docetaxel, p from 2 <0.001, and 69% versus 44% at 11HALO for doxorubicin, not significant) and highest day 60 survivalrate (100% versus 28% at 3 HALO for docetaxel, p from 2 <0.001and 89% versus 69% at 15 HALO for doxorubicin, not significant).Docetaxel-doxorubicin combinations were most effective followingdosing in the beginning of the rest span or short after theonset of the activity span, with regard to the rates of bothcomplete 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 docetaxelor doxorubicin and that of their combination varied largelyas a function of circadian dosing time. Single agent docetaxelat 7 HALO was the best treatment option in this model with regardto both tolerability and efficacy. This timing may correspondto the middle of the night in cancer patients.
Quote:
The rate of complete tumor inhibitions displayed large variationsas a function of both dose and dosing time for each single drug.Indeed, each dose level of docetaxel was more than 5-fold asactive at 7 HALO as at 3 HALO. A similar difference was foundfor the nontoxic dose of doxorubicin, with 7 HALO being alsothe most effective dosing time.
Quote:
Despite the overall rate of complete tumor inhibitions was largerwith combination A than with combination B (45 and 20%, respectively),the overall efficacy of docetaxel-doxorubicin was lower thanthat achieved with the highest dose tested for each single agent(docetaxel, 58%; doxorubicin, 96%). The tolerability of the most effective combination (A) was worsethan 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 toleratedbut less effective than combination A (45% versus 15% of completeregressions). Nevertheless, the survival rates on day 60 weresimilar (75% and 62%). Thus, the most active combination didnot improve the survival outcome of mice as compared with docetaxelor doxorubicin given as single agents at a nontoxic dose.
Quote:
In conclusion, the circadian dosing time of single agent docetaxelor doxorubicin or their combination profoundly influenced tolerabilityand antitumor efficacy in mice with MA13/C mammary adenocarcinoma.Each single agent produced the best results after administrationnear the middle of the rest span. Furthermore, single agentdelivery at its optimal dosing time displayed better tolerabilityand efficacy than both tested docetaxel-doxorubicin combinations.Although these results do not rule out a favorable therapeuticindex of other drug sequences or intervals in this model, theysupport the investigation of the clinical relevance of chronotherapyof human breast cancer. The therapeutic index of single agentdocetaxel or doxorubicin would be expected to be improved aftertheir administration at night in cancer patients
Re: Circadian Rhythm, eating schedule etc and treatment
2002, Vol. 19, No. 1, Pages 21-41 Tumor-based rhythms of anticancer efficacy in experimental models
Teresa G. Granda*1 and Francis Lévi*21Hôpital Paul Brousse, INSERM EPI 0118 “Cancer Chronotherapeutics,” Université Paris XI, 14–16 Avenue Paul-Vaillant Couturier, Villejuif, 94800, France 2Hôpital Paul Brousse, INSERM EPI 0118 “Cancer Chronotherapeutics,” Université Paris XI, 14–16 Avenue Paul-Vaillant Couturier, Villejuif, 94800, France
Experimental tumor models constitute a prerequisite toward chronotherapy testing in cancer patients. Studies in experimental models are required to understand the relation between tumor rhythms and antitumor treatments efficacy. In healthy tissues, cell proliferation, and differentiation processes are regulated precisely and exhibit marked circadian rhythmicity. Experimental and human tumors can retain circadian rhythms or display altered oscillations. Healthy tissues can also display rhythm modifications, possibly related to cancer stage. Cellular rhythms modulate the metabolism of cytotoxic agents and the cellular response to them; hence, they determine the chronopharmacology of anticancer drugs. Circadian rhythms in host tolerability and/or cancer chemotherapy efficacy have been demonstrated with nontoxic doses of drugs in several experimental tumor models, while in other ones a circadian-time effect was only seen within a specific dose range. The usual coupling between tolerability and efficacy rhythms of anticancer agents has resulted in significant improvement of their therapeutic index. Results of laboratory animal studies have been extrapolated to the design of clinical cancer therapy trials involving a chronobiological approach.
Re: Circadian Rhythm, eating schedule etc and treatment
Timed meals and chemo may boost anti-cancer therapy
Megan Rauscher
Reuters Health
Last Updated: 2006-04-27 15:51:22 -0400 (Reuters Health)
NEW YORK (Reuters Health) - A team of scientists has demonstrated, for the first time to their knowledge, endogenous circadian rhythmicity in a primary tumor. The discovery might open up new treatment approaches to chronomodulated therapy -- adjusting the temporal pattern of drug delivery to improve the toxic-therapeutic ratio.
The team's studies also suggest that tumor rhythms are sensitive to temporal changes in feeding. "Perhaps by combining chronotherapy with treatments (such as restricted feeding) that can manipulate the phase of the tumor and the host rhythms, the benefits of this treatment approach can be further enhanced," lead scientist Dr. Alec J. Davidson told Reuters Health.
Using transgenic rats, Dr. Davidson, from the Morehouse School of Medicine in Atlanta and colleagues at the University of Virginia in Charlottesville, studied expression patterns of the circadian clock gene (Period 1) in hepatocellular carcinoma and adjacent normal liver tissue.
"This animal's tissues express firefly luciferase in proportion to Per1 gene expression, allowing us to measure molecular rhythms by merely recording light emission with very sensitive detectors," Dr. Davidson explained.
"This comparison revealed not only alterations in the tumor rhythms -- the clock ran faster in the isolated tumor than in healthy liver tissue -- but also that a robust clock still exists in the tumor," Dr. Davidson said.
To study the effects of restricted feeding on the circadian rhythms of liver tumors, hepatoma-bearing rats were fed ad libitum, or a single small meal at night, or the same meal during the day.
"Temporally restricting food availability to either day or night altered the phase of the rhythms in both healthy and malignant tissue," the scientists report in the April 1st issue of the International Journal of Cancer. However, the tumors were much less sensitive to the restricted feeding signal "resulting in markedly different phase relationships between host and tumor tissue as a function of mealtime."
In the night-fed rats, the tumors rhythms peaked earlier than the healthy liver, and in the day-fed rats, the tumors peaked later than the healthy liver.
"Because circadian clocks are known to modulate the sensitivity of many therapeutic cytotoxic targets, controlling meal timing might be used to increase the efficacy of treatment," the authors suggest. "Specifically, meal and treatment schedules could be designed to take advantage of coincident times of greatest tumor sensitivity and lowest sensitivity of host tissue damage."
Resetting Central and Peripheral Circadian Oscillators in Transgenic Rats
Shin Yamazaki,1* Rika Numano,2* Michikazu Abe,1* Akiko Hida,2 Ri-ichi Takahashi,3 Masatsugu Ueda,3 Gene D. Block,1 Yoshiyuki Sakaki,2 Michael Menaker,1 Hajime Tei2
In multicellular organisms, circadian oscillators are organized into multitissue systems which function as biological clocksthat regulate the activities of the organism in relation to environmentalcycles and provide an internal temporal framework. To investigatethe organization of a mammalian circadian system, we constructeda transgenic rat line in which luciferase is rhythmically expressedunder the control of the mouse Per1 promoter. Light emission fromcultured suprachiasmatic nuclei (SCN) of these rats was invariablyand robustly rhythmic and persisted for up to 32 days in vitro.Liver, lung, and skeletal muscle also expressed circadian rhythms,which damped after two to seven cycles in vitro. In response toadvances and delays of the environmental light cycle, the circadianrhythm of light emission from the SCN shifted more rapidly thandid the rhythm of locomotor behavior or the rhythms in peripheraltissues. We hypothesize that a self-sustained circadian pacemakerin the SCN entrains circadian oscillators in the periphery tomaintain adaptive phase control, which is temporarily lost followinglarge, abrupt shifts in the environmental light cycle. 1 NSF Center for Biological Timing and Department of Biology, University of Virginia, Charlottesville, VA 22903-2477, USA. 2 Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan. 3 Y.S. New Technology Institute Inc., 519 Shimoishibashi, Ishibashi-machi, Tochigi, 329-0500, Japan. * These authors contributed equally to this work. To whom correspondence should be addressed. E-mail: mm7e@virginia.edu (M.M.) or tei@ims.u-tokyo.ac.jp (H.T.). Read the Full Text
Dr. Bill Hrushesky "Successful Cancer Therapy Development: Beating the Odds by Respecting Human Circadian Organization"
Director, Research Service Line
VA Research and Development
Columbia, South Carolina
Dr. David Blask "Melatonin: An Integrative Chronobiotic Anticancer Therapy Whose Time Has Come"
Bassett Research Institute
Cooperstown, NY
Dr. Paolo Lissoni "Clinical Experience with Melatonin Alone or Combined with the Standard Anticancer Therapies in Medical Oncology"
Division of Radiation Oncology, San Gerardo Hospital
Milan, Italy
Hrushesky
Founded Medical Chronotherapeutics
Circadian rhythm can be tracked via wristband
Rise in rate and BP before rising as indicator of circadian rhythm
There is a universal pain cycle, presumed circadian
Radiation is targeted to G2 part of cell cycle, most prominent in afternoon Ovarian trial found best schedule of Dox in morning, Cisplatinum in evening
5 yr 44% survival in optimal schedule vs 11% when timing was reversed
Colorectal cancer trial
Circadian oriented delivery of 5FU (S phase agent) in evening/overnight best, allows increased dose.
Renal cancer treatment greatly optimized by circadian delivery
Hepatic arterial efficacy increased with chronotherapy Lissoni
02:28:32 melatonin for neuron dosages w/Il-2 , it produces Il-12
Other pineal gland hormones help too and are amplified by melatonin 02:35:00
Naltrexone beneficial
Low dose Il-2 helpful
IL-12 + Il-2 melatonin and total pineal replacement therapy 02:37:00 Objective response not everything, immune response contributes to overall survival 02:38:50 Rationale of melatonin-chemotherapy association in cancer
Increased efficacy
Prevention of lymphocyte damage, potebtial increased survival
Antioxidant induced increased cytotoxic activity of chemo and possible enhanced tumor rate
Prevention of toxicity
Thrombocytopenia, neurotoxicity, immunosuppression-related symptoms, asthenia
02:40:23 Melatonin increased efficacy amongst many chemos and cancers, taxol, gemcitabine etc
02:43:57
Rationale of melatonin-classical endocrine therapy
MLT stimulates endocrine receptor expression
Melatonin may inhibit tumor growth factor production
May reverse endocrine resistance
May have direct cytostatic action
Melatonin may modulate the expression of oncogenes and antioncogenes involved in regulating cancer cell hormone dependency
02:44:28 combined LHRH+ MLT therapy for metastatic prostate cancer
02:44:50 MBC results, Tamoxifen + 20mg melatonin
02:45:58 Tam + melatonin in non hormonal cancers
Future perspectives
MLT receptors
Other pineal hormones
Q&A
02:50:38
Q: type of light important?
Blaska: type of light at night very important to MLT suppression. Low light not so much.
Blue green most potent for suppression,low level red light ok, duration length important
Length of day extremes can effect
H: Doxo/Cis variation of circadian relationship seasonal. Incidence of cancer seasonal
Eg cervical peak seasonal and inverted phase in latitudes
Sexuality seasonality may influence, urbanization artificial lights, lack of light
Blaska: rodents nocturnal, humans diurnal. But both have nocturnal melatonin surge. (i.e. mouse circadian studies relevant) Artificial light during day much dimmer, night light brighter..modern life environment works against/reverses normal circadian tuning.>>
Q: depression and light
H: Tuning circadian response: : Darkness at night. MLT at night. bright light in morning, early exercise for early bed
Q: treatment
L: disease as well as chemo disrupts melatonin. Melatonin monitoring could be helpful biomarker
H: Beta blockers and other drugs inhibit melatonin
B: aging, then drugs, tv etc increase cancer in aging
H: aging might be tuned by tuning..healthy lifestyle
H: chronotherapy in dish dismissed in 70’s, focus became ablating rhythms instead of tapping into them
H: Melatonin peaks at puberty. By 40, very weak and then worse. Aging depression and cancer might be modulated by mlt
B: exercise and diet can effect nocturnal amount of mlt
*INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, Villejuif, F-94807, France
†Université Paris-Sud, UMR-S0776, Orsay, F-91405, France
‡Assistance Publique-Hôpitaux de Paris, Chronotherapy Unit, Department of Oncology, Hôpital Paul Brousse, Villejuif, F-94807, France
Abstract
The circadian clock orchestrates cellular functions over 24 hours, including cell divisions, a process that results from the cell cycle. The circadian clock and cell cycle interact at the level of genes, proteins, and biochemical signals. The disruption or the reinforcement of the host circadian timing system, respectively, accelerates or slows down cancer growth through modifications of host and tumor circadian clocks. Thus, cancer cells not only display mutations of cell cycle genes but also exhibit severe defects in clock gene expression levels or 24-hour patterns, which can in turn favor abnormal proliferation. Most of the experimental research actively ongoing in this field has been driven by the original demonstration that cancer patients with poor circadian rhythms had poor quality of life and poor survival outcome independently of known prognostic factors. Further basic research on the gender dependencies in circadian properties is now warranted, because a large clinical trial has revealed that gender can largely affect the survival outcome of cancer patients on chronotherapeutic delivery. Mathematical models further show that the therapeutic index of chemotherapeutic drugs can be optimized through distinct delivery profiles, depending on the initial host/tumor status and variability in circadian entrainment and/or cell cycle length. Clinical trials and systems-biology approaches in cancer chronotherapeutics raise novel issues to be addressed experimentally in the field of biological clocks. The challenge ahead is to therapeutically harness the circadian timing system to concurrently improve quality of life and down-regulate malignant growth.
Re: Circadian Rhythm, eating schedule etc and treatment
Vol. 301 No. 9, March 4, 2009
Timing Chemotherapy
Bridget M. Kuehn JAMA. 2009;301(9):924.
Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.
Scientists have found a biological mechanism that may explain why chemotherapy is more effective when given at certain times of the day. Previous evidence had suggested the circadian clock plays a role. In the current study, researchers from the University of North Carolina in Chapel Hill demonstrated how a specific DNA-repair mechanism regulated by the clock may explain the phenomenon (Kang T et al. Proc Natl Acad Sci U S A. 10.1073/pnas.0812638106 [published online ahead of print January 21, 2009]). The researchers measured the activity at various times of day of the nucleotide excision repair system in tissue from the mouse cortex. They found the system is most active in the afternoon and evening hours and least active in the morning. This may explain why chemotherapy is more effective in the morning because this system is less able to repair DNA damage in cancer cells. Because . . . [Full Text of this Article]
Circadian oscillation of nucleotide excision repair in mammalian brain 1. Tae-Hong Kang, 2. Joyce T. Reardon, 3. Michael Kemp and 4. Aziz Sancar,1 + Author Affiliations 1. Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599 1. Contributed by Aziz Sancar, December 11, 2008 (received for review December 3, 2008)
Abstract
The circadian clock regulates the daily rhythms in the physiology and behavior of many organisms, including mice and humans. These cyclical changes at molecular and macroscopic levels affect the organism's response to environmental stimuli such as light and food intake and the toxicity and efficacy of chemo- and radiotherapeutic agents. In this work, we investigated the circadian behavior of the nucleotide excision repair capacity in the mouse cerebrum to gain some insight into the optimal circadian time for favorable therapeutic response with minimal side effects in cancer treatment with chemotherapeutic drugs that produce bulky adducts in DNA. We find that nucleotide excision repair activity in the mouse cortex is highest in the afternoon/evening hours and is at its lowest in the night/early morning hours. The circadian oscillation of the repair capacity is caused at least in part by the circadian oscillation of the xeroderma pigmentosum A DNA damage recognition protein.
The peak concentration of 5-FU occurs in the early rest span in both species when the drug is infused continuously at a constant rate for up to a one week span (Le´vi & Schibler 2007).
The apparent coupling between the circadian rest–activity cycle and the specific mechanisms that give rise to 24 hour rhythms in the PK and PD of medications across species has been the basis for the chronotherapeutic schedules given to
cancer patients. As a working hypothesis, the expected times of least toxicity in cancer patients were extrapolated from those experimentally demonstrated in synchronized mice or rats (i.e. animals that were housed under a regulated, typically 12 hour light–12 hour dark environment), by referring them to the respective rest–activity cycle of each species, e.g. with approximately 12 hour time lag. For instance, in mice the least toxicity of 5-FU occurs approximately 5 hours after light onset in the animal quarters, and this was predicted to correspond
to 04.00 in human beings, adhering to sleep between 23.00 and 07.00 alternating with activity between 07.00 and 23.00.
Figure 3. Rationale of circadian-based delivery of 5-FU and oxaliplatin, chronomodulated drugdelivery
schedule and main results in cancer patients. (a) Circadian organization of cell cycle phase distribution in humans. In healthy human beings, the proportion of S-phase cells rises and reaches a maximum near 16.00 daily in oral mucosa as well as in bone marrow. Since 5-FU is most toxic for S-phase cells, exposure at this time should be avoided in order to reduce toxic effects for both of these proliferating healthy tissues, which represent the main toxicity targets of this drug. (b) ChronoFLO schedule. Chronomodulated sinusoidal delivery schedules have been designed based on experimental data in mice as well as the rhythms in cell cycle phase distribution and detoxification processes shown in humans. Here, the reference chronoFLO5 consists in the sinusoidal delivery of 5-FU and leucovorin, for 12 hours with a peak at 04.00 in alternation with oxaliplatin for 12 hours with a peak at 16.00 for five
consecutive days every three weeks. This schedule has been administered with programmable-in-time multichannel electronic pumps and validated in patients with metastatic colorectal cancer registered in phase I, II and III clinical trials. (Adapted from Bjarnason et al. (2001), Bjarnason & Jordan (2002), Smaaland et al. (2002), Le´vi (2001) and Le´vi et al. (2007b).)
Review. Circadian clocks and cancer therapeutics 3583
Phil. Trans. R. Soc. A (2008)
The availability of portable multichannel programmable-in-time pumps constituted a key technological step for the implementation of cancer chronotherapeutics.
Indeed, these electronic devices make possible the continuous
chronomodulated delivery of up to four different medications in the patients’ usual activities in- or outside the home. The clinical relevance of the chronotherapy principle was first tested in a large population of patients with metastatic colorectal cancer, using standard methods of clinical trials.
(d ) Chronotherapeutics of colorectal cancer
Metastatic colorectal cancer is the second most common cause of cancer deaths in both men and women. Until the early 1990s, conventional treatment methods offered few therapeutic options other than the reference combination chemotherapy of 5-FU–leucovorin (LV). The chronomodulated protocols involved the time qualified infusion of 5-FU and LV, eventually associated with oxaliplatin, an active drug that was first recognized as such through chronotherapeutic development (Levi et al. 1992). The maximum delivery rate of 5-FU–LV was scheduled during sleep at 04.00 and of oxaliplatin at 16.00, based upon the extrapolations from experimental laboratory rodent modelling data. Courses lasted 4 or 5 days and were repeated every second or third week (figure 3b). The tolerability, maximum dose intensities and anti-tumour activity of this chronotherapeutic schedule were evaluated in phase I, II and III clinical trials involving over 2000 patients with metastatic colorectal cancer. In a first phase II single institution trial, 93 patients, 46 of whom had received previous chemotherapy, were treated with the chronomodulated combination of 5-FU–LV and oxaliplatin for 5 days every
three weeks. This new treatment achieved a 58 per cent response rate, a figure that was approximately fourfold higher than that produced by the conventional daily bolus of 5-FU–LV for 5 days every three weeks (Le´vi et al. 1992).
Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer
F Bertheault-Cvitkovic, A Jami, M Ithzaki, PD Brummer, S Brienza, R Adam, F Kunstlinger, H Bismuth, JL Misset and F Levi
Centre de Chronotherapie, Service des Maladies Sanguines, Immunitaires et Tumorales, France.
PURPOSE: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2. RESULTS: World Health Organization (WHO)- modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. CONCLUSION: This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.
Chronomodulated capecitabine in combination with short-time oxaliplatin: a Nordic phase II study of second-line therapy in patients with metastatic colorectal cancer after failure to irinotecan and 5-flourouracil
C. Qvortrup1,2,*, M. Yilmaz3, D. Ogreid4, A. Berglund5, L. Balteskard6, J. Ploen7, T. Fokstuen8, H. Starkhammar9, H. Sørbye10, K. Tveit11 and P. Pfeiffer11 Department of Oncology, Odense University Hospital 2 Institute of Clinical Research, University of Southern Denmark, Odense 3 Department of Oncology, Aalborg University Hospital, Aalborg, Denmark 4 Department of Oncology, Rogaland Central Hospital, Stavanger, Norway 5 Department of Oncology, Radiology and Clinical Immunology University Hospital, Uppsala University Hospital, Uppsala, Sweden 6 Department of Oncology, Tromso University Hospital, Tromso, Norway 7 Department of Oncology, Vejle Hospital, Vejle, Denmark 8 Department of Oncology and Pathology, Karolinska Hospital, Stockholm 9 Department of Oncology, Linkoping University Hospital, Linkoping, Sweden 10 Department of Oncology, Haukeland University Hospital, Bergen 11 Department of Oncology, Ullevål University Hospital, Oslo, Norway *Correspondence to: Dr C. Qvortrup, Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C 5000, Denmark. Tel: +45 65413147; Fax: +45 66135477; E-mail: camilla.qvortrup@ouh.regionsyddanmark.dk Background: Oxaliplatin in combination with capecitabine prolongssurvival in patients with metastatic colorectal cancer (mCRC).Chronomodulation might reduce toxicity and improve efficacy. Patients and methods: A phase II study examining chronomodulatedXELOX30 (XELOX30chron): oxaliplatin: 130 mg/m2 on day 1, asa 30-min infusion between 1 and 3 p.m. Capecitabine: total dailydose of 2000 mg/m2, 20% of the dose between 7 and 9 a.m. and80% of the dose between 6 and 8 p.m. in patients with mCRC resistantto irinotecan. Seventy-one patients were enrolled. Responserate was 18%; median progression-free survival 5.1 months andmedian overall survival (OS) 10.2 months. Platelet count andperformance status were significantly correlated to OS in multivariateanalyses. Neurotoxicity grade 2 and 3 was seen in 25% and 2%of patients, respectively, other grade 3 toxic effects wereas follows: nausea 6%, vomiting 3%, diarrhoea 12% (3% experiencedgrade 4) and palmoplantart erytem 9%. Conclusion: XELOX30chron is a convenient second-line regimenwith efficacy and safety profile similar to other oxaliplatinschedules. To further investigate chronomodulated XELOX, wehave started a Nordic randomised phase II study comparing XELOX30and XELOX30chron as first-line therapy in patients with mCRC.
Key words: capecitabine, chronotherapy, metastatic colorectal cancer, oxaliplatin, short-time infusion, XELOX
Received for publication October 24, 2007. Revision received December 28, 2007. Accepted for publication December 31, 2007.
Re: Circadian Rhythm, eating schedule etc and treatment
Cancer. 2009 Nov 1;115(21):4990-9. Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer.
Bouchahda M, Adam R, Giacchetti S, Castaing D, Brezault-Bonnet C, Hauteville D, Innominato PF, Focan C, Machover D, Lévi F.
Chronotherapy Unit, Medical Oncology Department, Hepatobiliary Center, Public Assistance Hospital of Paris, Paul Brousse Hospital, Villejuif, France. mohamed.bouchahda@pbr.aphp.fr
BACKGROUND:: Hepatic arterial infusion (HAI) chemotherapy delivers a high concentration of drugs both to liver metastases and to healthy liver with specific, limiting, hepatobiliary toxicities. Relevant detoxification and cellular proliferation pathways are controlled by the molecular circadian clock in normal liver but not in advanced tumors. In this article, the authors report their experience with chronomodulated HAI chemotherapy as rescue therapy in heavily pretreated patients who had metastatic colorectal cancer. METHODS:: Data from all consecutive patients with colorectal cancer liver metastases who received HAI with chronomodulated, multidrug chemotherapy regimens in the authors' center after failure on standard chemotherapy were reviewed for efficacy and safety. RESULTS:: Twenty-nine patients were treated, including 76% with liver metastasis only and 24% with liver and lung metastases. Seventy-five percent of patients had received > or =3 chemotherapy lines, including intravenous, chronomodulated chemotherapy in 59% of patients. Patients received a median of 4 HAI courses (range, 1-9 courses). The most frequent grade (according to National Cancer Institute of Canada Common Toxicity Criteria [version 3]) 3 and 4 nonhematologic toxicities were vomiting, diarrhea, abdominal pain, and fatigue. No severe hematologic or hepatic toxicities and no chemical cholangitis were reported. An objective tumor response was observed in 10 patients (34.5%), including 4 patients who subsequently underwent R0 or R1 hepatic resection. The median progression-free survival and overall survival were 4.5 months (95% confidence limits, 2.4-6.5 months) and 18 months (95% confidence limits, 5.8-30.2 months), respectively. CONCLUSIONS:: HAI chronomodulated chemotherapy had well tolerated activity in selected, heavily pretreated patients, and the authors believe it deserves to be assessed prospectively in clinical trials among patients who have less advanced disease. Cancer 2009. (c) 2009 American Cancer Society.
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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 
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