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Research Articles: Therapeutics

Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index

¹ Medical Chronobiology Laboratory, Dorn Research Institute, William Jennings Bryan Dorn Veterans Affairs Medical Center, ² School of Medicine, and ³ School of Public Health, University of South Carolina, Columbia, South Carolina

Requests for reprints: William J.M. Hrushesky, William Jennings Bryan Dorn Veterans Affairs Medical Center, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209. Phone: 803-695-6825; Fax: 803-695-6829. E-mail: william.hrushesky{at}med.va.gov

Dysregulated cellular proliferation is a characteristic property of cancer. We show that, despite this fact, cancers maintain high amplitude, circadian rhythms in their growth, DNA synthesis, and mitosis. These patterns are accompanied by the daily traverse of BMAL-1 protein between the cytoplasm, where it is produced, and nucleus, where it influences timing of cancer cell proliferation. This core clock gene product gates cancer cell proliferation by coordinating clock-controlled proteins, thymidylate synthase [thymidylate synthase activity (TSA) cell DNA replication], WEE-1 (cell mitosis), and vascular endothelial growth factor (growth). 5-Fluorouracil (5-FU)–induced host bone marrow and gut toxicity and tumor shrinkage following administration at six equispaced times of day allowed determination of circadian relationships among tumor growth, relevant clock, and clock-controlled proteins and dependence of 5-FU target availability (TSA) in normal and cancer tissues and resultant 5-FU toxic-therapeutic index. The time of day (hours after lights on) of low TSA in each tissue and tumor is respectively associated with greatest toxicity to that tissue and greatest tumor shrinkage. 5-FU treatment near daily awakening results in least damage to bone marrow and gut, greatest antitumor effect, and best survival. This time of day is associated with maximum tumor nuclear BMAL-1 and total cell WEE-1 protein. The described chain of events, for the first time, links cancer cell clock proteins, cancer cell DNA synthesis, proliferation, TSA, and 5-FU toxic-therapeutic index, explaining the dependence of cancer outcome on circadian timing of 5-FU. [Mol Cancer Ther 2006;5(8):2023–33]

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Received 3/30/06; revised 5/18/06; accepted 6/ 7/06.

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