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Circadian clock genes may provide targets for new cancer drugs

American Association For Cancer Research (AACR) : 18 November, 2003  (Company News)
A tumor's growth may be controlled by a complex, gene-controlled 'clock, and jamming that 'clock' can offer a new way to fight cancer, according to two studies presented today at the International Conference on Molecular Targets and Cancer Therapeutics organized by the American Association of Cancer Research, National Cancer Institute and European Organisation for Research and Treatment of Cancer in Boston.
Tumor cell circadian clock genes are rhythmically expressed in coordination with rhythmic circadian growth and thereby may represent new therapeutic targets: Abstract 698

Recent research suggests that at least eight central 'clock' genes coordinate many basic functions such as cell proliferation and apoptosis in circadian time, or within each day, according to researchers from the Dorn Veterans Administration Medical Center and the University of South Carolina. Shaojin You, M.D., Ph.D., assistant professor, and his colleagues undertook the first study to establish a relationship between circadian clock gene expression and the growth rate of tumors.

'These results demonstrate that tumor growth itself, as well as cellular and molecular measures of cancer growth, are organized within circadian time,' said Dr. You. 'Taken in the context of other recent studies, this work indicates that circadian clock genes and their products potentially represent novel targets for the control of cancer growth.'

In these studies, some 30 female mice kept on an alternating 12-hour light and 12-hour dark schedule were injected with tumor cells; the rate of tumor growth was subsequently measured to determine the impact of circadian rhythms.

The results showed that 'tumors grew on average twice as fast in the 'daily activity/dark circadian phase' than during the 'sleep/light phase' of the [24 hour] circadian cycle,' the team reported. The tumor mitotic index, a measure of the proportion of cancer cells actively dividing, was also most prominent during the activity phase of the circadian cycle.

The scientists then analyzed the expression of circadian clock genes in tumor cells and in normal (liver) cells from the mice. Cancer cells exhibited altered circadian expression of some of their circadian clock genes (per1, per2), but retained circadian organization in others (BMAL-1). The scientists also found that the circadian organization of clock gene expression in a normal tissue and sleep activity cycles of the mice were not disrupted by the tumor.

Control of DNA damage response by the molecular clock: Abstract 740

A gene known to regulate circadian rhythms also acts as a tumor suppressor by regulating the mechanisms by which cells stop dividing after DNA damage, said researchers from Baylor College of Medicine. The results offer significant insights into the initiation of cancer, and also suggest a new treatment target.

The gene called Period2 controls the circadian or 24-hour cycle in the cells of mice. In the laboratory of the molecular and human genetics department at Baylor College of Medicine in Houston, Loning Fu, Ph.D., assistant professor, and her colleagues have shown that mice that lack this gene are prone to developing cancer.

'Cancer cells and normal cells follow different circadian rhythms,' said Dr. Fu. 'We found that the circadian clock controls how cells react to DNA damage during the 24-hour cycle.' These controls are responsible for initiating a process called apoptosis that results in the death of the damaged cell.

'The cell with damaged DNA becomes cancerous because apoptosis does not occur,' said Dr. Fu. 'We found that the response of normal cells to DNA damage is time dependent in a live organism. When the circadian gene is mutated, the cells become resistant to radiation-induced apoptosis.'

This factor could play a role in the timing of treatment with anti-cancer drugs, which often damage DNA. 'Now patients undergo treatment at any time that is convenient to them and the physician,' said Dr. Fu. 'The responses of normal and tumor cells to anti-cancer drugs during the circadian period should be studied so that doctors could potentially time the delivery of therapy to coincide with the time period when patients' normal cells are less sensitive than tumor cells to DNA damage.'
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