Circadian Biological Time Influences the Effect Adriamycin Has on DNA Synthesis in Mouse Bone Marrow, Ileum and Tongue but not Ehrlich Ascites Carcinoma

Er, Burns

doi:10.1159/000226068

Cited by 9 publications

(5 citation statements)

References 6 publications

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“…ADM administered at 16 HALO (within 3-4 hr of the usual daily awakening) reduced tumor size more effectively than that administered at 4 HALO (within 3-4 hr of the usual daily sleep onset). These results are quite consistent with the previous observations that ADM is less toxic and more effective in mice and in human cancer patients when administered shortly after daily awakening (Lkvi et al, 1980;Hrushesky, 1985;Burns, 1985). The most reasonable explanation for the variation of efficacy in the present study is that the delivery of anti-cancer drug to tumor tissues probably increases at night since the main factor determining the efficacy of drug delivery to tumor tissues is tumor tissue blood flow (Suzuki et al, 1984;Jain and Ward-Hartley, 1984;Vaupel et al, 1989), which reaches its greatest value at night in rat S.C. tumors (Hori et al, 1992).…”

Section: Discussionsupporting

confidence: 92%

Timing of cancer chemotherapy based on circadian variations in tumor tissue blood flow

Hori

Zhang

et al. 1996

Int. J. Cancer

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Blood flows of normal tissues (subcutis, liver, kidney cortex, bone marrow) and tumor tissues (SLC) were measured during a daytime period (3-9 HALO) and a nighttime period (15-21 HALO) by the hydrogen clearance technique. Rats were subjected to an artificial light-dark cycle with light from 7 A.M. to 7 P.M. In all normal tissues, there were no significant differences between average tissue blood flows in 2 different time zones, while tumor tissue blood flow increased significantly in the nighttime. Based on this functional characteristic of tumor microcirculation, anti-tumor effects were compared between a group in which ADM was administered at 4 HALO and a group in which it was administered at 16 HALO. The therapeutic effect of ADM on rats administered at I 6 HALO was significantly greater, particularly in large tumors, than that on rats administered at 4 HALO. The main reason for this therapeutic improvement may be due to the selective increase in delivery of anti-cancer drugs to tumor tissues brought about by a circadian increase in tumor tissue blood flow. o 1996 Wiley-Liss, Inc. We have discovered circadian fluctuations in tissue blood flow of S.C. rat tumors (Hori et al., 1992), and the time during which tumor tissue blood flow increases coincides with the time during which tumor growth becomes more rapid (Hori et al., 1995). It has also been reported that there are circadian fluctuations in DNA synthesis of tumor cells (Smaaland et al., 1993; Hrushesky and Bjarnason, 1993). The fact that tumor tissue blood flow and tumor growth vary during a 24-hr time period supports the idea that there may be an optimal time for the administration of anti-cancer drugs. Because commonly used anti-cancer drugs exert their greatest effects when cancer cells are actively dividing and/or in specific phases of the cell cycle, if an anti-cancer drug could be delivered to tumor tissue when the proliferation of cancer cells is at its peak, then its therapeutic effect would be further increased. The purpose of this study was to confirm the importance of the circadian timing of cancer chemotherapy. We measured the tissue blood flows of normal organs and tumors during the nighttime and the daytime. Furthermore, we investigated whether the efficacy of cancer chemotherapy is enhanced by administering anti-cancer drugs when tumor tissue blood flow increases. MATERIAL AND METHODS Rats and tumor Male Donryu rats (Crj-Donryu; Nippon Charles-River, Yo-kohama, Japan), weighing approximately 300-340 g each, were used for tissue blood flow measurements. The same strain of rats, weighing approximately 230-260 g each, was used for the chemotherapy experiments. Rats were caged in an air-conditioned room at a temperature of 25 & 1°C and given food and water ad libitum. For 3 weeks prior to measurement they were subjected to an artificial light-dark cycle, with light from 7 A.M. to 7 P.M. Rodents are nocturnal. In fact, rats under this condition were in full activity during the nighttime, though they slept well during the daytime. The tumor cells...

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Section: Discussionsupporting

confidence: 92%

Timing of cancer chemotherapy based on circadian variations in tumor tissue blood flow

Hori

Zhang

et al. 1996

Int. J. Cancer

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“…The cytotoxic effect of doxorubicin depends on the doxorubicin concentration (AUC) in cells and blood (Simoyama 1975). Chronopharmacokinetics of doxorubicin were reported in 18 patients treated concomitantly with 5-fluorouracil, doxorubicin and cyclophosphamide in the morning or evening (Canal et al 1991). The clearance of doxorubicin decreased significantly during the rest phase compared with the active phase, resulting in a longer elimination half-life and an increase in the AUC.…”

Section: Discussionmentioning

confidence: 99%

“…The hepatic blood flow showed a significant 24-h variation with a peak in the early morning and a trough in the early evening in healthy subjects (Lemmer & Nold 1991). The 24-h variation of hepatic blood flow was related to that of doxorubicin clearance in breast cancer patients (Canal et al 1991). The hepatic blood flow in rats showed a significant 24-h variation with a peak in the active phase and a trough in the rest phase (Labrecque et al 1988).…”

Section: Discussionmentioning

confidence: 99%

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Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats

Ohdo

Shin

et al. 2003

Journal of Pharmacy and Pharmacology

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Cardiac toxicity caused by doxorubicin (adriamycin) is a serious dose-limiting factor in the clinical situation. However, the influence of doxorubicin dosing time has not been clarified from the viewpoints of cardiotoxic development and its mechanism. In this study, we have investigated the dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity after repeated administration of doxorubicin in rats. When doxorubicin (5 mg kg(-1), i.p.) was administered every seven days (total of 30 mg kg(-1)) at 3, 9, 15 or 21 h after the light was turned on (HALO), toxic death was significantly higher in the 9 HALO treated group than the other groups. When doxorubicin was injected every seven days for 28 days at 9 or 21 HALO, we measured the levels of creatine kinase, malondialdehyde (MDA; an index of lipid peroxide), and glutathione peroxidase (GPx) as markers of cardiotoxicity. On days 14 and 28, creatine kinase levels were significantly higher in the 9-HALO group compared with the 21-HALO group (P< 0.01, respectively). On day 14, MDA levels increased significantly in the 9 HALO group compared with the 21 HALO group (P< 0.01). A single dose of doxorubicin was administered at 9-h or 21-h after the light was turned on to investigate the dosing-time-dependent difference of the pharmacokinetics. The area under the plasma time-concentration curve showed a significant increase at 9 HALO compared with 21 HALO (P< 0.05). These results suggested that the dosing-time-dependent difference of cardiotoxicity induced by doxorubicin was closely related to the daily variation of doxorubicin pharmacokinetics. In conclusion, the choice of optimal dosing time based on the chronopharmacokinetics of doxorubicin may decrease the cardiotoxicity and enable the practice of effective and safe chemotherapy of doxorubicin.

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“…It has been found that the wound-healing impairment depends on direct inhibition of mitosis in local fibroblasts and keratinocytes or myelosuppression of platelets and inflammatory cells, which are important in recovery from injury [ 6 - 8 ]. The toxicity and efficacy of adriamycin can be modulated by the selection of optimal dosing times in a chronotherapeutic manner [ 9 , 10 ], as is the case for other drugs as well [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Temporal variation in the recovery from impairment in adriamycin-induced wound healing in rats

Ağuş¹,

Dinç

Başgut³

et al. 2007

J Circadian Rhythms

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Circadian Biological Time Influences the Effect Adriamycin Has on DNA Synthesis in Mouse Bone Marrow, Ileum and Tongue but not Ehrlich Ascites Carcinoma

Cited by 9 publications

References 6 publications

Timing of cancer chemotherapy based on circadian variations in tumor tissue blood flow

Timing of cancer chemotherapy based on circadian variations in tumor tissue blood flow

Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats

Temporal variation in the recovery from impairment in adriamycin-induced wound healing in rats

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