Author/Editor		Tozer, Gillian M; Prise, Vivien E; Wilson, John; Čemažar, Maja; Shan, Siqing; Dewhirst, Mark W; Barber, Paul R; Vojnović, Borivoj; Chaplin, David J
Title		Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability
Type		članek
Source		Cancer Res
Vol. and No.		Letnik 61, št. 17
Publication year		2001
Volume		str. 6413-22
Language		eng
Abstract		The tumor vascular effects of the tubulin destabilizing agent disodium combretastatin A-0 3-0-phosphate (CA-4-P) were investigated in the rat P22 tumor growing in a dorsal skin flap window chamber implanted into BD9 rats. CA-4-P is in clinical trial as a tumor vascular targeting agent. In animal tumors, it can cause the shut-down of blood tlow, leading to extensive tumor cell necrosis. However, the mechanisms leading to vascular shut-down are still unknown. Tumor vascular effects were visualized and monitored on-line before and after the administration of two doses of CA-4-P (30 and 100 mg/kg) using intravital microscopy. The combined effect of CA-4-P and systemic nitric oxide synthase (NOS) inhibition using Nomega-nitro-L-arginine (L-NNA) was also assessed, because this combination has been shown previously to have a potentiating effect. The early effect of CA-0-P on tumor vascular permeability to albumin was determined to assess whether this could be involved in the mechanism of action of the drug. Tumor blood fl0ow reduction was extremely rapid after CA-4-P treatment, with red cell velocity decreasing throughout the observation period and dropping to <5% of the starting value by 1 h. NOS inhibition alone caused a 50% decrease in red cell velocity, and the combined treatment of CA-0-P and NOS inhibition was approximately additive. The mechanism of blood tlow reduction was very different for NOS inhibition and CA-4-P. That of NOS inhibition could be explained by a decrease in vessel diameter, which was most profound on the arteriolar side of the tumor circulation. In contrast, the effects of CA-4-P resembled an acute intlammatory reaction resulting in a visible loss of a large proportion of the smallest blood vessels. There was some return of visible vasculature at 1 h after treatment, but the blood in these vessels was static or nearly so, and many of the vessels were distended. (Abstract truncated at 2000 characters).
Descriptors		CARCINOSARCOMA NEOPLASMS, EXPERIMENTAL STILBENES RATS DRUG SYNERGISM MICROSCOPY, FLUORESCENCE NEOVASCULARIZATION, PATHOLOGIC NITRIC OXIDE NITRIC-OXIDE SYNTHASE NITROARGININE