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.