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Title: Alterations in vascular architecture and permeability following OXi4503 treatment.
Austin Authors: Chan, Lie Sam;Malcontenti-Wilson, Caterina;Muralidharan, Vijayaragavan ;Christophi, Christopher 
Affiliation: Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 1-Jan-2008
Publication information: Anti-cancer Drugs; 19(1): 17-22
Abstract: OXi4503 retards tumor growth in a dose-dependent manner and improves survival in a murine model of colorectal liver metastases. This agent causes extensive vascular shutdown by selectively altering the tubulin cytoskeleton within the endothelial cells of tumor vessels. The destruction of tumor vessels is incomplete, however, and tumor revascularization occurs after the treatment. This study evaluates the pattern of microcirculatory changes and alterations to the ultrastructural properties of the tumor vasculature that result from OXi4503 treatment. Male CBA mice were induced with liver metastases via an intrasplenic injection of a murine-derived colorectal cell line. After administering a single intraperitoneal dose of OXi4503, changes in tumor perfusion, microvascular architecture and permeability were assessed at various time points. One hour after a 100-mg/kg dose of OXi4503, a significant decrease in the percentage of tumor perfusion (63.96+/-1.98 in controls versus 43.77+/-2.71 in treated mice, P<0.001) was observed, which was still evident 5 days after the treatment. Substantial tumor microvascular damage and minimal normal liver injury were observed. Tumor vascular permeability was significantly elevated 45 min after the OXi4503 treatment (67.5+/-3.60 in controls versus 80.5+/-2.24 microg/g, P<0.05). The findings suggest that OXi4503 selectively targets tumor vessels and causes immediate microvascular destruction. Even at the maximum tolerated dose, however, residual patent tumor vessels were still present after treatment, implying incomplete tumor destruction. A combination of OXi4503 with other chemotherapeutic modalities might achieve complete tumor eradication and improve long-term survival.
Gov't Doc #: 18043126
DOI: 10.1097/CAD.0b013e3282f077a1
Type: Journal Article
Subjects: Angiogenesis Inhibitors.pharmacology
Blood Vessels.drug effects.pathology
Capillaries.drug effects.pathology
Capillary Permeability.drug effects
Colorectal Neoplasms.chemically induced.pathology
Evans Blue
Laser-Doppler Flowmetry
Liver Neoplasms.blood supply.secondary
Mice, Inbred CBA
Microscopy, Confocal
Microscopy, Electron, Scanning
Regional Blood Flow.drug effects
Tissue Fixation
Appears in Collections:Journal articles

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