Circadian organization of thymidylate synthase activity in normal tissues:A possible basis for 5-fluorouracil chronotherapeutic advantage

Fluoropyrimidines induce cytotoxicity, in part, by inhibiting the prolifera tion-coordinated enzyme thymidylate synthase (TS), which is essential for D NA synthesis. Tumor TS levels are clinically predictive of post-surgical tu mor recurrence and of response to fluoropyrimidine chemotherapy. Fluoropyri midine drug toxicity and efficacy each vary reproducibly in humans and anim als, depending upon their circadian timing. In vivo, normal tissues and som e tumor tissues exhibit circadian coordination of cellular proliferation. W e therefore asked whether TS activity is coordinated rhythmically throughou t the day in the normal proliferative tissues most damaged by fluoropyrimid ine drugs. To assess tissue and time of day TS activity differences, we har vested normal tissues from female mice living on a 12:12 hr light:dark sche dule at each of 6 different equispaced times throughout a 24 hr cycle and m easured TS catalytic activity. We observed up to 10-fold differences in viv o in TS activity among different normal tissue types, roughly paralleling t heir proliferative state and relative fluoropyrimidine sensitivity. In norm al tissues most damaged by fluoropyrimidines (bone marrow, small intestinal mucosa and oral mucosa/tongue). TS activity varies up to 2-fold throughout each day. In bone marrow, the circadian pattern of TS activity parallels t he circadian rhythm in proliferation in this tissue. This circadian organiz ation of TS, one of the primary fluoropyrimidine targets in normal tissues, probably contributes in vivo to the time of day differences in the toxic-t herapeutic ratio of circadian-timed fluoropyrimidine drug therapy. Int. J, Cancer 88:479-485, 2000. (C) 2000 Wiley-Liss, Inc.