Alterations in vascular architecture and permeability following OXi4503 treatment.
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.
Department of Surgery, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia. l.chan11@pgrad.unimelb.edu.au
Lie Sam
LS
Chan
Cathy
C
Malcontenti-Wilson
Vijayaragavan
V
Muralidharan
Christopher
C
Christophi
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects* / Q000473:pathology; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002273:Carcinogens; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000473:pathology; D004127:Dimethylhydrazines; D011756:Diphosphates / Q000494:pharmacology*; D005070:Evans Blue; D017078:Laser-Doppler Flowmetry; D008113:Liver Neoplasms / Q000098:blood supply* / Q000556:secondary*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D018613:Microscopy, Confocal; D008855:Microscopy, Electron, Scanning; D012039:Regional Blood Flow / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D016707:Tissue Fixation
D020533:Angiogenesis Inhibitors; D002273:Carcinogens; D004127:Dimethylhydrazines; D011756:Diphosphates; C465018:Oxi 4503; D013267:Stilbenes; D005070:Evans Blue