[Rich66]

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." http://www.sciencemag.org/cgi/conten...t/288/5466/682 Int J Cancer 2006;118:1623-1627. Science 28 April 2000: Vol. 288. no. 5466, pp. 682 - 685 DOI: 10.1126/science.288.5466.682 Prev | Table of Contents 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 Tei 2 In multicellular organisms, circadian oscillators are organized into multitissue systems which function as biological clocks that regulate the activities of the organism in relation to environmental cycles and provide an internal temporal framework. To investigate the organization of a mammalian circadian system, we constructed a transgenic rat line in which luciferase is rhythmically expressed under the control of the mouse Per1 promoter. Light emission from cultured suprachiasmatic nuclei (SCN) of these rats was invariably and 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 to advances and delays of the environmental light cycle, the circadian rhythm of light emission from the SCN shifted more rapidly than did the rhythm of locomotor behavior or the rhythms in peripheral tissues. We hypothesize that a self-sustained circadian pacemaker in the SCN entrains circadian oscillators in the periphery to maintain adaptive phase control, which is temporarily lost following large, 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