Inhibition of integrin alpha5beta1 function with a small peptide (ATN-161) plus continuous 5-FU infusion reduces colorectal liver metastases and improves survival in mice.

Abstract

Integrin alpha(5)beta(1) is expressed on activated endothelial cells and plays a critical role in tumor angiogenesis. We hypothesized that a novel integrin alpha(5)beta(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 alpha(5)beta(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.

• Authors: Oliver Stoeltzing, Wenbiao Liu, Niels Reinmuth, Fan Fan, Graham C Parry, Alexander A Parikh, Marya F McCarty, Corazon D Bucana, Andrew P Mazar, Lee M Ellis
• Journal: International journal of cancer (Int J Cancer) Vol. 104 Issue 4 Pg. 496-503 (Apr 20 2003) ISSN: 0020-7136 [Print] United States
• PMID: 12584749 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright 2003 Wiley-Liss, Inc.

Chemical References

• Angiogenesis Inhibitors
• Integrin alpha5beta1
• Oligopeptides
• Fluorouracil
• acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide

Topics

• Angiogenesis Inhibitors (administration & dosage)
• Animals
• Apoptosis (drug effects)
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Colorectal Neoplasms (drug therapy, pathology)
• Endothelium, Vascular (cytology, drug effects)
• Fluorouracil (administration & dosage)
• Integrin alpha5beta1 (antagonists & inhibitors, physiology)
• Liver Neoplasms (blood supply, prevention & control, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Oligopeptides (administration & dosage)