<i>In vivo</i> Analysis of Tumor Vascularization in the Rat

Hori, Kentaro; Suzuki, Maroh; Tanda, Shigeru; Saito, Sachiko

doi:10.1111/j.1349-7006.1990.tb02562.x

Cited by 62 publications

(38 citation statements)

References 18 publications

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“…Additionally, most tumor blood vessels have an irregular diameter and an abnormal branching pattern. For example, Hori and colleagues have shown that terminal arterioles in rat hepatoma or lung carcinomas approximated 50 branches per 0.1 mm 2 , as compared to 14 per 0.1 mm 2 in normal tissues (55). Interestingly, a similar phenomenon occurs in leukemia: irregular and complex branching of microvessels has been observed in leukemic bone marrow, compared with the single, straight microvessels without branching in normal bone marrow (56).…”

Section: Factors Impacting Tumor Distributionmentioning

confidence: 98%

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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Abstract. The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

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Section: Factors Impacting Tumor Distributionmentioning

confidence: 98%

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Tabrizi

Bornstein

Suria

2009

AAPS J

267

185

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“…For direct observation of changes in normal arterioles and tumour vessels caused by AC7700, transparent chambers (Hori et al, 1990) were implanted in dorsal skin flaps of rats under aseptic conditions. The chamber used in the present experiment was a 'sandwich' system (Yamaura and Sato, 1974) in which each chamber consists of a pair of identical titanium frames containing a circular quartz glass window 300 mm thick.…”

Section: Transparent Chamber Assaysmentioning

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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“…Rat transparent chambers (Hori et al, 1990) were implanted in dorsal skin flaps under aseptic conditions. Each chamber consisted of two identical titanium frames containing a circular quartz glass window 300 mm thick.…”

Section: Measurement Of Tbfmentioning

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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In vivo Analysis of Tumor Vascularization in the Rat

Cited by 62 publications

References 18 publications

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

Biodistribution Mechanisms of Therapeutic Monoclonal Antibodies in Health and Disease

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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