Variation of growth rate of a rat tumour during a light-dark cycle: correlation with circadian fluctuations in tumour blood flow

Hori, Kentaro; Zhang, Q. H.; Li, H. C.; Saito, Sachiko

doi:10.1038/bjc.1995.227

Cited by 29 publications

(23 citation statements)

References 16 publications

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“…Following these beats, three sets of clock-controlled protein increase and decrease: WEE-1 gates tumor cell mitosis; TSA gates 5-FU sensitivity and therapeutic index; and VEGF, along with other clockcontrolled genes, coordinates cancer blood flow and growth (29,30). This work shows for the first time the more or less complete chain of events responsible for repeated experimental and clinical findings that time of day proliferation-targeted anticancer drug, such as 5-FU, is given, determines its therapeutic index (31 -33).…”

Section: Discussionmentioning

confidence: 99%

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

Wood

Du-Quiton

You

et al. 2006

Molecular Cancer Therapeutics

101

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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.

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Section: Discussionmentioning

confidence: 99%

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

Wood

Du-Quiton

You

et al. 2006

Molecular Cancer Therapeutics

101

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“…Although SLC and LY80 showed almost the same growth potential in the transparent chamber and showed almost the same reaction after AC7700 administration, we chose SLC rather than LY80 for vital microscopic observations. We did so because when SLC is growing in transparent chambers, demarcation between the edge of the growing tumour and the normal tissue is clear (Hori et al, 1995), and therefore the change in normal arterioles and tumour vessels after AC7700 administration can easily be recognised.…”

Section: Rats and Tumoursmentioning

confidence: 99%

Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis

2003

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We previously reported that a novel combretastatin A-4 derivative, AC7700, has remarkable antitumour effects because of an irreversible stasis of tumour blood flow (TBF) and subsequent loss of nutrient supply to tumour tissue. Since early 2002, under the new designation AVE8062, AC7700 has undergone clinical trials in Europe and the US. Questions remain, however, concerning how AC7700 blocks TBF and why the TBF stasis does not recover. In this study, using a rat tumour LY80, a variant of Yoshida sarcoma, we examined whether TBF cessation after AC7700 administration is due to a direct action of the agent on tumour blood vessels. We constructed electrodes that can drop a small quantity of the drug solution directly at the site of blood flow measurement and inserted them subcutaneously and into the tumour. We compared the blood flow responses of normal vessels and tumour vessels after administration of 10-ml doses of various concentrations (0.2, 1, 10, and 50 mg ml À1 ) of the AC7700 solution. In addition, we assessed TBF stasis after i.v. and intra-arterial 10 mg kg À1 AC7700 administration in an LY80-induced kidney tumour. To determine why the TBF stasis is irreversible, we observed AC7700-induced changes in host arterioles and the tumour vascular network of the Sato lung carcinoma using a vital microscopic rat transparent chamber. Since an increase in tumour interstitial fluid pressure brings about a decrease in TBF, we also measured 10 mg kg À1 AC7700-induced changes in this pressure. The sensitivity of the blood flow response after intratumoral application of AC7700 was markedly higher in normal vessels relative to tumour vessels. Intra-arterial administration of AC7700 did not have stronger effects on TBF stasis than did i.v. administration. Intravital microscopy showed that AC7700 induced a powerful and long-lasting constriction of host arterioles, so that complete stasis of blood flow occurred in downstream vessels, which supplied blood to tumours. Owing to this stasis, the lumens of numerous tumour vessels narrowed or completely disappeared, and numerous erythrocytes stagnated in drainage vessels of the tumour vascular network. Haemolysis of these erythrocytes occurred after 2 -3 h, resulting in complete thrombosis. There was no indication of reperfusion in vessels showing haemolysis. This haemolysis is thought to be the main cause for the irreversibility of TBF stasis. Since the tumour interstitial fluid pressure decreased after i.v. AC7700 administration, the possibility of stasis of TBF being caused by tumour vascular compression was excluded. All these results strongly suggest that the main target of AC7700 is host arterioles and that the stasis of TBF induced by AC7700 is not triggered by a direct action of the drug on tumour vessels.

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“…and s.c. transplantations, respectively. We chose SLC for vital microscopic observations because when the tumour is implanted in transparent chambers, demarcation between the edge of the growing tumour and normal tissue is clear, and therefore the change in microtumour size after therapy can easily be measured (Hori et al, 1995). Experiments were performed with the animals anaesthetised in a controlled-temperature box fitted with a suction duct.…”

Section: Rats and Tumourmentioning

confidence: 99%

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

2002

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In a previous study, we used subcutaneous LY80 tumours (a subline of Yoshida sarcoma), Sato lung carcinoma, and methylcholanthrene-induced primary tumours, to demonstrate that a novel water-soluble combretastatin A-4 derivative, AC7700, abruptly and irreversibly stopped tumour blood flow. As a result of this interrupted supply of nutrients, extensive necrosis was induced within the tumour. In the present study, we investigated whether AC7700 acts in the same way against solid tumours growing in the liver, stomach, kidney, muscle, and lymph nodes. Tumour blood flow and the change in tumour blood flow induced by AC7700 were measured by the hydrogen clearance method. In a model of cancer chemotherapy against metastases, LY80 cells (2610 6 ) were injected into the lateral tail vein, and AC7700 at 10 mg kg 71 was injected i.v. five times at intervals of 2 days, starting on day 7 after tumour cell injection. The number and size of tumours were compared with those in the control group. The change in tumour blood flow and the therapeutic effect of AC7700 on microtumours were observed directly by using Sato lung carcinoma implanted in a rat transparent chamber. AC7700 caused a marked decrease in the tumour blood flow of all LY80 tumours developing in various tissues and organs and growth of all tumours including lymph node metastases and microtumours was inhibited. In every tumour, tumour blood flow began to decrease immediately after AC7700 administration and reached a minimum at approximately 30 min after injection. In many tumour capillaries, blood flow completely stopped within 3 min after AC7700 administration. These results demonstrate that AC7700 is effective for tumours growing in various tissues and organs and for metastases. We conclude that tumour blood flow stanching induced by AC7700 may become an effective therapeutic strategy for all cancers, including refractory cancers because the therapeutic effect is independent of tumour site and specific type of cancer.

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Variation of growth rate of a rat tumour during a light-dark cycle: correlation with circadian fluctuations in tumour blood flow

Cited by 29 publications

References 16 publications

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

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

Microvascular mechanisms by which the combretastatin A-4 derivative AC7700 (AVE8062) induces tumour blood flow stasis

A novel combretastatin A-4 derivative, AC7700, strongly stanches tumour blood flow and inhibits growth of tumours developing in various tissues and organs

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