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

Abstract

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.

Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors

“…Ombrabulin (AVE8062, AC-7700) is an analog of the water-soluble VDA combretastatin A4 phosphate (CA4P). These drugs act by disrupting the architecture of established tumor blood vessels following binding to the colchicine site of tubulin, inhibiting polymerization, and resulting in reorganization of the cytoskeleton and changes in cell shape (1,2). Ombrabulin shows cytotoxic activity by blocking cell proliferation, induces endothelial cell detachment, and causes constriction of the arteriolar system.…”

Induction of tumour blood flow stasis and necrosis: a new function for epinephrine similar to that of combretastatin A-4 derivative AVE8062 (AC7700)

“…AVE8062 (Hori and Saito, 2003). AVE8062 also induces an increase in systemic blood pressure (Hori et al, 1999), similar to that produced by epinephrine, but the hypertension itself does not cause the stanching of TBF.…”

“…Previously, we showed by means of analysis of microcirculation and intravital microscopic observations that the vascular occlusion is not due to a direct effect of AVE8062 on tumour vessels, but rather is likely due to an indirect effect on host arterioles (Hori and Saito, 2003). Thus, AVE8062 causes a lasting increase in vascular resistance of host arterioles, and this effect produces a marked and persistent fall in the perfusion pressure of the downstream vessels feeding the tumour.…”

“…Many red blood cells then form aggregates in the lumens of drainage vessels, and after 2 -3 h haemolysis of the red blood cells and subsequent thrombosis occur. This is thought to be the irreversible process of tumour vessel occlusion caused by AVE8062 (Hori and Saito, 2003).…”

“…Arteries can be clasiffied according to Strahler's method (1957): capillaries branching off from terminal arterioles are assigned index number 1, terminal arterioles are defined as a2; arterioles are then defined as a3, a4, a5 and so on, as one proceeds from the periphery . Both AVE8062 and epinephrine raise the vascular resistance of host arterioles a3, a4, and a5, and halt the blood flow in the downstream vessels that feed the tumour (a2 vessels modified because of the influence of the tumour) (Hori et al, 1993;Hori and Saito, 2003). In contrast, methoxamine (Hori et al, 1993), norepinephrine, dopamine, and metaraminol have less effect on vascular resistance in a3, a4, and a5 vessels, and do not block blood flow in tumour-feeding vessels (data not shown).…”