Effect of Vascular Targeting Agent Oxi4503 on Tumor Cell Kinetics in a Mouse Model of Colorectal Liver Metastasis

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. The differential characteristic between the tumor vasculature and normal blood vessels has allowed the development of agents that can specifically target these abnormalities. Vascular targeting agents (VTA) are a large group of compounds that specifically target established tumor vasculature (1). These agents disrupt the tumor endothelium and occlude tumor blood flow, resulting in extensive ischemic necrosis of the tumor. Oxi4503 is a VTA belonging to a family known as the combretastatins. Originally derived from the bark of the South African Willow Combretum caffrum (2, 3), members from this family have been shown to be highly selective for tumor vasculature and cause significant tumor destruction with minimal side-effects (4-10). Oxi4503 selectively targets the endothelial cell cytoskeleton and causes morphological alterations which lead to tumor vessel occlusion and subsequent cellular necrosis (11). Despite causing significant tumor necrosis, the pattern of cell death is not homogenous and following cessation of Oxi4503 treatment, tumor regrowth occurs (9, 10, 12). The underlying mechanisms of cell death and patterns of necrosis remain to be elucidated. Using a well established murine model of CRC liver metastases, the aim of this study was to determine the optimal dose of Oxi4503 causing growth retardation and tumor cell necrosis and to investigate the changes in the patterns of tumor cell death, apoptosis, proliferation and microvessel density following treatment with Oxi4503.