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DNC News
J Natl Cancer Inst. 2002 May 1;94(9):690-7. Host circadian clock as a control point in tumor progression. Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu X, Claustrat B, Hastings MH, Levi F.
Institut National de la Sante et de la Recherche Medicale, Equipe Propre INSERM 0118 Cancer chronotherapeutics, Universite Paris XI, Paul Brousse Hospital, Villejuif, France.
BACKGROUND: The circadian timing system controlled by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of motor activity and adrenocortical secretion. An alteration in these rhythms is associated with poor survival of patients with metastatic colorectal or breast cancer. We developed a mouse model to investigate the consequences of severe circadian dysfunction upon tumor growth. METHODS: The SCN of mice were destroyed by bilateral electrolytic lesions, and body activity and body temperature were recorded with a radio transmitter implanted into the peritoneal cavity. Plasma corticosterone levels and circulating lymphocyte counts were measured (n = 75 with SCN lesions, n = 64 sham-operated). Complete SCN destruction was ascertained postmortem. Mice were inoculated with implants of Glasgow osteosarcoma (n = 16 with SCN lesions, n = 12 sham-operated) or pancreatic adenocarcinoma (n = 13 with SCN lesions, n = 13 sham-operated) tumors to determine the effects of altered circadian rhythms on tumor progression. Time series for body temperature and rest-activity patterns were analyzed by spectral analysis and cosinor analysis. Parametric data were compared by the use of analysis of variance (ANOVA) and survival curves with the log-rank test. All statistical tests were two-sided. RESULTS: The 24-hour rest-activity cycle was ablated and the daily rhythms of serum corticosterone level and lymphocyte count were markedly altered in 75 mice with complete SCN destruction as compared with 64 sham-operated mice (two-way ANOVA for corticosterone: sampling time effect P<.001, lesion effect P =.001, and time x lesion interaction P<.001; for lymphocytes P =.001,.002, and.002 respectively). Body temperature rhythm was suppressed in 60 of the 75 mice with SCN lesions (P<.001). Both types of tumors grew two to three times faster in mice with SCN lesions than in sham-operated mice (two-way ANOVA: P<.001 for lesion and for tumor effects; P =.21 for lesion x tumor effect interaction). Survival of mice with SCN lesions was statistically significantly shorter compared with that of sham-operated mice (log-rank P =.0062). CONCLUSIONS: Disruption of circadian rhythms in mice was associated with accelerated growth of malignant tumors of two types, suggesting that the host circadian clock may play an important role in endogenous control of tumor progression.
PMID: 11983758 [PubMed - indexed for MEDLINE]
To view the full text of this article go to: http://jncicancerspectrum.oupjournals.org/cgi/content/full/jnci;94/9/690
Chronobiol Int. 2002 Jan;19(1):1-19. From circadian rhythms to cancer chronotherapeutics. Levi F.
INSERM EPI 0118 Cancer Chronotherapeutics, Universite Paris XI and Chronotherapy Group, European Organisation for Research and Treatment of Cancer, Hjpital Paul Brousse, Villejuif, France.
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 2,000 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.
Publication Types: Review Review, Tutorial
PMID: 11962669 [PubMed - indexed for MEDLINE]
-------------------------------------------------------------------------------- Chronobiol Int. 2002 Jan;19(1):237-51. Circadian chemotherapy for gynecological and genitourinary cancers. Kobayashi M, Wood PA, Hrushesky WJ.
WJB Dorn VA Medical Center/Department of Developmental Biology and Anatomy, The University of South Carolina School of Medicine, Columbia 29209, USA.
The circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, tumor control, and host survival. Optimally timed cancer chemotherapy with doxorubicin or pirarubicin ( 06:00 h) and cisplatin ( 18:00 h) enhanced the control of advanced ovarian cancer while minimizing side effects, and increased the response rate in metastatic endometrial cancer. Therapy of metastatic bladder cancer with doxorubicin-cisplatin was made more tolerable by this same circadian approach resulting in a 57% objective response rate. This optimally timed therapy is also effective in the adjuvant setting, decreasing the expected frequency of metastasis from locally advanced bladder cancer. Circadian fluorodeoxyuridine (FUDR) continuous infusion (70% of the daily dose given between 15:00 h and 21:00 h) has been shown effective for metastatic renal cell carcinoma resulting in 29% objective response and stable disease of more than 1 yr duration in the majority of patients. Toxicity is reduced markedly when FUDR infusion is modulated to circadian rhythms. In a multicenter trial in patients with metastatic renal cell cancer, patients were randomized to a flat or a circadian-modified FUDR infusion. This study confirmed a significant difference in toxicity and dose intensity, favoring the circadian-modified group. Hormone refractory metastatic prostate cancer has been treated with circadian-timed FUDR chemotherapy; however, without objective response. Biological agents such as interferon-alpha and IL-2 have shown low but effective disease control in metastatic renal cell cancer, however, with much toxicity. Each of these cytokines shows circadian stage dependent toxicity and efficacy in model systems. In summary, the timing of anthracycline, platinum, and fluoropyrimidine-based drug therapies during the 24h is relevant to the toxic therapeutic ratio of these agents in the treatment of gynecologic and genitourinary cancers. Publication Types: Review Review, Tutorial PMID: 11962679 [PubMed - indexed for MEDLINE]
Lancet. 1997 Sep 6;350(9079):681-6. Comment in: Lancet. 1997 Nov 1;350(9087):1325-6. Randomised multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Levi F, Zidani R, Misset JL.
Hopital Paul Brousse, Villejuif , France .
BACKGROUND: The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals. METHODS: We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat. FINDINGS: On enrollment, we found significant imbalances in two characteristics-abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21.5% [95% CI 13.7-31.2], p = 0.003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p < 0.0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15.0% [9.5-25.7], p < 0.01). Median time to treatment failure was 6.4 months on chronotherapy and 4.9 months on constant-rate infusion (p = 0.006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15.9 vs 16.9 months and 22% vs 21%, respectively). INTERPRETATION: Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy. Publication Types: Clinical Trial Multicenter Study Randomized Controlled Trial PMID: 9291901 [PubMed - indexed for MEDLINE]
J Pharm Pharmacol. 1999 Aug;51(8):891-8. Cancer chronotherapy. Levi F.
Laboratoire Rythmes Biologiques & Chronotherapeutique, Hopital Paul Brousse, Villejuif , France .
The cytotoxicity of more than thirty anticancer drugs varies by more than 50% as a function of dosing time along the 24-h time-scale in laboratory animals . Mechanisms involve circadian changes in cellular metabolism and proliferation processes, as well as drug pharmacokinetics. Moreover, the administration of chemotherapy at the least toxic time usually achieves best antitumour efficacy in experimental tumour models . Here we review experiences in utilising these phenomena in the optimization of cancer chemotherapy in the clinic. Chronotherapy has been administered to 1500 patients with metastatic colorectal cancer using 5-fluorouracil and leucovorin with or without oxaliplatin. Sinusoidal chronomodulated delivery of 2- or 3-drug chemotherapy was performed in the patient's home or during usual activities, with a computer-programmed multi-reservoir pump. Courses lasted 4-5 days and were repeated every 14-21 days. Three-drug chronotherapy proved largely superior to flat infusion with respect to both tolerability and antitumour efficacy. The better tolerability of chronotherapy further allowed an increment of both 5-fluorouracil and oxaliplatin doses, which in turn further improved objective tumour response rate to 66%. This enabled surgical removal of previously inoperable metastases and the achievement of > 20% survival at three years. Second generation programmable-in-time pumps have simplified chronotherapy administration and decreased its costs. A broad use of fully ambulatory chronotherapy requires thorough definitions of drug stability, and compatibility with pump reservoirs and other medications. Publication Types: Review Review, Tutorial PMID: 10504026 [PubMed - indexed for MEDLINE]
Chronobiol Int. 2002 Jan;19(1):77-100. Chronobiology of the mammalian response to ionizing radiation. Potential applications in oncology.
Haus E.
Division of Pathology, HealthPartners Medical Group, Regions Hospital, University of Minnesota, St Paul 55101, USA. erhard.x.haus@healthpartners.com
Ionizing radiation from all sources under appropriate conditions leads to cell death and tissue damage. It is used in cancer treatment under the assumption of a higher radiosensitivity of the fast dividing tumor cells as compared with adjacent host tissues. The radiosensitivities of proliferating host tissues like bone marrow and gastrointestinal lining epithelium are dose limiting. Since these host tissues and many tumors show circadian and other periodicities in their cell proliferation, the timing of radiation treatment according to host and/or tumor rhythms is expected to improve the toxic/therapeutic ratio of the treatment. The experimental data on the chronobiology of radiation exposure show circadian rhythmicity in radiation response after whole body irradiation in mice and rats with highest toxicity in light-dark 12h:12h synchronized animals during their daily activity span. Bone marrow toxicity as well as gastrointestinal epithelial damage show circadian rhythms in part due to radiation damage to the stem cells involved and especially in the intestine also due to damage to the microvasculature. Chronoradiotherapy of malignant tumors seems promising, alone or in combination with response modifiers, provided the host and potential tumor rhythms can be monitored.
Publication Types: Review Review, Academic PMID: 11962688 [PubMed - indexed for MEDLINE]
Chronobiol Int. 2002 Jan;19(1):207-19. Chronotherapy of colorectal cancer. Giacchetti S.
Chronotherapy Unit, Federation des maladies Sanguines Immunitaires et tumorales and INSERM EPI 0118, Hjpital Paul Brousse, Villejuif, France. . sylvie.giacchetti@pbr.ap-hop-paris.fr
Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I-III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU-leucovorin-L-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases.
Publication Types: Clinical Trial Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Randomized Controlled Trial PMID: 11962676 [PubMed - indexed for MEDLINE]
Hepatogastroenterology. 2001 Mar-Apr;48(38):320-2. Chronotherapy of colorectal cancer metastases. Levi F, Giacchetti S, Zidani R, Brezault-Bonnet C, Tigaud JM, Goldwasser F, Misset JL.
Centre de Chronotherapie, Federation des Maladies Sanguines, Immunitaires et Tumorales Hopital Paul Brousse, Villejuif , France . chronbio@club-internet.fr
Chronotherapy has consisted in the adaptation of chemotherapeutic drug delivery to circadian (approximately 24-hour) rhythms. This can be achieved in fully ambulatory patients using multichannel programmable pumps. Up to approximately 1500 patients with metastatic colorectal cancer have been registered in one of 15 trials testing the relevance of this treatment method with 5-fluorouracil +/- leucovorin +/- oxaliplatin. Chronotherapy was shown as significantly less toxic and more effective than constant rate infusion in 2 consecutive multicenter trials. High efficacy and good tolerability permitted secondary surgical resection of previously inoperable metastases, with apparent survival improvement (3-year survival > or = 20%) and cures in some patients. This strategy is currently undergoing further testing within the European Organization for Research and Treatment of Cancer. Nevertheless, combining chronotherapy with surgery of colorectal cancer metastases can be readily offered to patients as a safer therapeutic option for optimizing outcome.
Publication Types: Review Review, Tutorial PMID: 11379299 [PubMed - indexed for MEDLINE]
Ann Oncol. 2001 May;12(5):681-4. A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer. Penberthy DR , Rich TA, Shelton CH 3rd, Adams R, Minasi JS, Jones RS.
Department of Radiation Oncology, University of Virginia Health Sciences Center , Charlottesville 22901 , USA .
BACKGROUND: Dose limiting acute toxicity from chemoradiation for pancreatic cancer occurs in 15% -20% of patients treated with post-operative adjuvant therapy. Reported here is a pilot study using chronomodulated infusional 5-fluorouracil (5-FU) chemoradiation (CIC) for pancreatic cancer, a treatment designed to reduce normal tissue toxicity and maintain efficacy, with specific evaluation of acute and late morbidity, patterns of disease progression, and survival. PATIENTS AND METHODS: Twenty-three patients with adenocarcinoma of the pancreas were treated with 5-FU CIC between January 1997 and September 1999. The median age was 64, and there were 9 males and 14 females. Six patients were considered unresectable and seventeen others were treated post-operatively. The median external beam irradiation dose was 50.4 Gy. 5-FU infusion was given five days per week (300 mg/m2/d) and the median total dose was 8.4 g/m2. The chronomodulated 5-FU infusion consists of a low basal infusion rate for 16 hours followed by an eight-hour escalating-deescalating infusion peaking at 10 p.m. All patients were followed from the time of initial diagnosis until last follow-up or death; the median follow-up was 16 months. RESULTS: No RTOG grade 3 or 4 hematologic toxicity occurred. Twelve of seventeen patients treated postoperatively have been controlled locally, and seven patients have no evidence of disease. The median survival is 28 months and one-year actuarial survival is 88% in the group of resected patients. The 6 patients treated for unresectable disease have a median survival of 13 months. CONCLUSIONS: Acute toxicity of 5-FU CIC appears to be less frequent and less severe than that reported with flat infusional or bolus 5-FU based chemoradiation used for adjuvant post-operative therapy for pancreatic cancer. This method may warrant further examination, as it may be attractive for the elderly or those who cannot tolerate the toxicity associated with standard post-operative treatment protocols.
Publication Types: Clinical Trial
PMID: 11432628 [PubMed - indexed for MEDLINE]
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