Inhibition of integrin α5β1 function with a small peptide (ATN‐161) plus continuous 5‐FU infusion reduces colorectal liver metastases and improves survival in mice

Abstract Integrin α 5 β 1 is expressed on activated endothelial cells and plays a critical role in tumor angiogenesis. We hypothesized that a novel integrin α 5 β 1 antagonist, ATN‐161, would inhibit angiogenesis and growth of liver metastases in a murine model. We further hypothesized that combining ATN‐161 with 5‐fluorouracil (5‐FU) chemotherapy would enhance the antineoplastic effect. Murine colon cancer cells (CT26) were injected into spleens of BALB/c mice to produce liver metastases. Four days thereafter, mice were given either ATN‐161 (100 mg/kg, every 3rd day) or saline by intraperitoneal injection, with or without combination of continuous‐infusion 5‐FU (100 mg/kg/2 weeks), which was started on day 7. On day 20 after tumor cell inoculation, mice were killed and liver weights and number of liver metastases were determined. A follow‐up study on survival was also conducted in which mice were randomized to receive ATN‐161, 5‐FU or ATN‐161+5‐FU. Combination therapy with ATN‐161+5‐FU significantly reduced tumor burden (liver weight) and number of liver metastases ( p <0.02). Liver tumors in the ATN‐161 and ATN‐161+5‐FU groups had significantly fewer microvessels ( p <0.05) than tumors in the control or 5‐FU‐treated groups. Unlike treatment with either agent alone, ATN‐161+5‐FU significantly increased tumor cell apoptosis and decreased tumor cell proliferation ( p <0.03) and improved overall survival ( p <0.03, log‐rank test). Targeting integrin α 5 β 1 in combination with 5‐FU infusion reduced liver metastases formation and improved survival in this colon cancer model. The enhancement of antineoplastic activity from the combination of anti‐angiogenic therapy and chemotherapy may be a promising approach for treating metastatic colorectal cancer. © 2003 Wiley‐Liss, Inc.