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

Abstract

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.

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

“…AC7700 works both in rapidly proliferating transplanted tumours and in relatively slowly proliferating primary tumours induced by chemical carcinogens (Hori et al, 2001). Recently, such effectiveness was confirmed in tumours growing within internal organs, including the liver, kidney, and stomach, as well as in metastatic lymph nodes and small 2.5-mm-diameter foci (Hori et al, 2002), which suggests that these effects might be obtained in all types of solid tumours. Since early 2002, AC7700 has been undergoing clinical trials in Europe and the US under the new code name AVE8062.…”

Vascular disrupting agents in clinical development

“…Preclinical studies have shown rapid and irreversible vascular shutdown in various different orthotopic tumour models. Complete stasis of blood flow was observed after 30 min, whereas blood flow in normal tissues was compromised but returned to pretreatment levels within 24 h. Tumour cell proliferation in different models was suppressed after drug infusion (Hori et al, 2002). So far only one phase-I single-agent study has been published in which nine patients received 48 infusions of AVE8062 (Table 1) (Tolcher et al, 2003).…”

Vascular effects dominate solid tumor response to treatment with combretastatin A‐4‐phosphate

“…8,9 CA4P and other VDAs are highly selective for rodent and human tumors where they cause significantly greater vascular damage compared with normal tissues. [8][9][10][11][12] The mechanisms through which VDAs elicit their anti-tumor activity are conceptually different from those of classic chemotherapeutic agents that directly target the tumor cell component and kill cells by apoptosis or related mechanisms. 13 Although the precise molecular pathways that drive tumor vascular collapse are not yet fully understood, in vitro analyses have shown that VDAs act through binding to tubulin resulting in microtubule depolymerization, triggering morphological changes in endothelial cells that include increased blebbing and contraction, contributing to the disruption of cell-to-cell junctions and increased permeability.…”