RELATIONSHIP BETWEEN CIRCADIAN-DEPENDENT TOXICITY OF 5-FLUORODEOXYURIDINE AND CIRCADIAN-RHYTHMS OF PYRIMIDINE ENZYMES - POSSIBLE RELEVANCE TO FLUOROPYRIMIDINE CHEMOTHERAPY

Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fl uorodeoxyuridine (FdUrd) although the biochemical mechanisms are not f ully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzym e in the thymidine-phosphorylation pathway, is the first enzyme in the anabolism of FdUrd. Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2) , is the rate-limiting enzyme in the pyrimidine catabolic pathway and has been shown to be the key enzyme in FdUrd catabolism. The present s tudy examined the relationship between the suggested circadian variati on in FdUrd toxicity and potential circadian variations in the activit y of these enzymes. Initial studies in Sprague-Dawley rats confirmed t hat the time of FdUrd administration affected death rate and other dru g-related toxicities including loss of body weight, diarrhea, and bone marrow suppression, with the least toxicity and highest survival rate being observed in rats receiving FdUrd at 12:00 noon and 4:00 p.m. an d the greatest toxicity and lowest survival rate at 12:00 midnight and 4:00 a.m. Statistical analysis revealed a circadian pattern in FdUrd toxicity (Cosinor analysis, P < 0.001). In subsequent studies with the same species, we simultaneously measured TK and DPD activities in sev eral tissues at various times over 24 h. Under standardized light cond itions (lights on, 6:00 a.m. to 6:00 p.m.; lights off, 6:00 p.m. to 6: 00 a.m.), with sampling at 4-h intervals (4:00 and 8:00 a.m.; 12:00 no on; 4:00 and 8:00 p.m., and 12:00 midnight), a circadian variation in TK activity was observed (P < 0.0001, Cosinor analysis) in bone marrow , intestinal mucosa, liver, and spleen. In the same group of animals, a circadian pattern of DPD activity in liver and bone marrow was also observed (Cosinor analysis, P < 0.0001) that was inverse compared to t he circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed cir cadian variation in FdUrd toxicity was correlated with the circadian v ariation of TK activity and inversely correlated with DPD activity (Pe arson correlation analysis, P < 0.05). Based on the above data, we con clude that the circadian pattern of TK and DPD activity may explain th e observed circadian variation in toxicity as the time of FdUrd admini stration is varied. These results may be useful in the design of impro ved chemotherapeutic regimens using time-modified administration of Fd Urd.