[This statement in the abstract: “From 12 hr, the vessel structure was completely destroyed” is more strongly worded than the comment in OXGN’s PR (see previous post) that blood flow was reduced by as much as 90%. I do not understand the reason for the disparity.
Also notable is the degree to which a burst of VEGF aids in the permeability of the endothelial cells to the drug. VEGF was at one time known as a “permeability factor” before it took on its existing moniker as a “growth factor” –Dew]
>> ABSTRACT Received: 18 August 2003; Accepted: 12 February 2004
Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis
Yezhou Sheng 1 * , Jianyi Hua 1, Kevin G. Pinney 2, Charles M. Garner 2, Robert R. Kane 2, Joseph A. Prezioso 3, David J. Chaplin 3, Klaus Edvardsen 1Department of Cell and Molecular Biology, Section for Tumor Immunology, University of Lund, Lund, Sweden 2Department of Chemistry and Biochemistry and the Center for Drug Discovery, Baylor University, Waco, TX, USA 3OXiGENE Inc., Waltham, MA, USA
The mechanism of tumor cell killing by OXI4503 was investigated by studying vascular functional and morphological changes post drug administration. SCID mice bearing MHEC5-T hemangioendothelioma were given a single dose of OXI4503 at 100 mg/kg. Tumor blood flow, measured by microsphere fluorescence, was reduced by 50% at 1 hr, and reached a maximum level 6-24 hr post drug treatment. Tumor vascular permeability, measured by Evan's blue and hemoglobin, increased significantly from 3 hr and peaked at 18 hr. The elevated tumor vessel permeability was accompanied by an increase in vascular endothelial growth factor (VEGF) from 1 hr post drug treatment. Immunohistochemical staining for CD31 and laminin showed that tumor blood vessels were affected as early as 3 hr but more prominent from 6 hr. From 12 hr, the vessel structure was completely destroyed. Histopathological and double immunohistochemical staining showed morphological change and induction of apoptosis in endothelial cells at 1-3 hr, followed by tumor cell necrosis from 6-72 hr. There were no statistically significant changes of Evan's blue and hemoglobin contents in liver tissue over the time course. These results suggest that OXI4503 selectively targets tumor blood vessels, and induces blood flow shutdown while it enhances tumor blood vessel permeability. The early induction of endothelial cell apoptosis leads to functional changes of tumor blood vessels and finally to the collapse of tumor vasculature, resulting in massive tumor cell necrosis. The time course of the tumor vascular response observed with OXI4503 treatment supports this drug for development as a stand alone therapy, and also lends support for the use of the drug in combination with other cancer therapies. <<
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