Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: Possible relevance to fluoropyrimidine chemotherapy

Ruiwen Zhang, Zhihong Lu, Robert B Diasio, Seng Jaw Soong, Robert B. Diasio

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Abstract

Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme 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 study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-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. and 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 several tissues at various times over 24 h. Under standardized light conditions (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 noon; 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 the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.

Original languageEnglish (US)
Pages (from-to)2816-2822
Number of pages7
JournalCancer Research
Volume53
Issue number12
StatePublished - Jun 15 1993
Externally publishedYes

Fingerprint

Floxuridine
Circadian Rhythm
Drug Therapy
Enzymes
Dihydrouracil Dehydrogenase (NADP)
Bone Marrow
Light
Survival Rate
pyrimidine
Thymidine Kinase
Liver
Intestinal Mucosa
Drug-Related Side Effects and Adverse Reactions
Thymidine
Sprague Dawley Rats
Diarrhea
Spleen
Body Weight
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes : Possible relevance to fluoropyrimidine chemotherapy. / Zhang, Ruiwen; Lu, Zhihong; Diasio, Robert B; Soong, Seng Jaw; Diasio, Robert B.

In: Cancer Research, Vol. 53, No. 12, 15.06.1993, p. 2816-2822.

Research output: Contribution to journalArticle

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abstract = "Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme 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 study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-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. and 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 several tissues at various times over 24 h. Under standardized light conditions (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 noon; 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 the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.",
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T2 - Possible relevance to fluoropyrimidine chemotherapy

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AU - Diasio, Robert B

AU - Soong, Seng Jaw

AU - Diasio, Robert B.

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N2 - Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme 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 study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-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. and 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 several tissues at various times over 24 h. Under standardized light conditions (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 noon; 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 the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.

AB - Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme 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 study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-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. and 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 several tissues at various times over 24 h. Under standardized light conditions (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 noon; 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 the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.

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