Effect of vascular targeting agent Oxi4503 on tumor cell kinetics in a mouse model of colorectal liver metastasis.

Abstract

BACKGROUND: Oxi4503 has been shown to inhibit tumor growth and improve survival in an animal model of colorectal (CRC) liver metastases. This agent appears to selectively target the endothelial cytoskeleton with resultant vessel occlusion and tumor necrosis. MATERIALS AND METHODS: This study evaluated the pattern of tumor necrosis caused by Oxi4503, with particular emphasis on patterns of cell proliferation and apoptosis in a murine model of CRC liver metastases. RESULTS: A single dose of Oxi4503 caused immediate tumor vasculature collapse and subsequently tumor necrosis. There was widespread central necrosis with evidence of viable tumor cells at the periphery. Alterations in the number and spatial pattern of tumor cells undergoing apoptosis and the rate of cellular proliferation were also observed following treatment. Microvessel density was reduced following treatment, however patent vessels were still observed within the necrotic core. CONCLUSION: Although Oxi4503 caused significant tumor destruction, synergistic treatment with cytotoxic and/or anti-angiogenic agents should be considered in order to achieve complete tumor eradication and long-term survival.