B183
OXi4503 shows efficacy as a single agent in colorectal liver metastases in nude mice, and potential for enhancing antibody-targeted therapies
R Barbara Pedley, Uzma Qureshi, Ethaar El-Emir, Elena Fidarova, Geoffrey Boxer, Mathew Robson
UCL Cancer Institute, London, UK
Background
Radioimmunotherapy (RIT) is showing promise in the clinical treatment of colorectal liver metastases. RIT studies, using 131I anti-CEA antibody in nude mice bearing orthotopic colorectal tumours, produced responses but no cures. The vascular disrupting agent (VDA) OXi4503 interacts with tubulin to cause vascular shut-down, leading to central tumour necrosis but leaving a viable peripheral rim which continues to grow. We therefore investigated the efficacy of OXi4503 as a single agent, and its potential for future combined studies with antibody-targeted therapies.
Method
We employed the SW1222 human colorectal cancer model, grown as liver metastases in nude mice, to investigate the effect of repeat OXi4503 dosing on tumour growth. Groups of 6 mice received either Oxi4503 or no treatment. Oxi4503 (40mg/kg/dose), was given intraperitoneally on days 1, 3 and 5, and then at weekly intervals for 7 weeks. A further group of mice were injected with Hoechst 33342 (perfusion marker) and pimonidazole (hypoxia marker), and tumours studied for pathophysiological changes following therapy.
Results
Untreated tumours were generally viable and well perfused. Following OXi4503, tumour perfusion had ceased, and hypoxia developed, by 3 hours with no effect on normal liver. By 24 hours both large and small tumours showed massive central necrosis, but with a thin surviving rim of viable tumour cells. Repeat dosing significantly (P<0.001) prolonged survival, with 2 mice alive at 7 months. Combined therapy studies with this promising VDA (eg with anti-angiogenesis antibodies) are currently underway.
Acknowledgments
Supported by Cancer Research UK, European Union FP6 STROMA, OXi4503 supplied by OXiGENE.
