Abstract
Integrin α5β1 is expressed on activated endothelial cells and plays a critical role in tumor angiogenesis. We hypothesized that a novel integrin α5β1 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 α5β1 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.
Original language | English (US) |
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Pages (from-to) | 496-503 |
Number of pages | 8 |
Journal | International Journal of Cancer |
Volume | 104 |
Issue number | 4 |
DOIs | |
State | Published - Apr 20 2003 |
Externally published | Yes |
Keywords
- Angiogenesis
- Colon cancer
- Integrins
- Liver metastases
ASJC Scopus subject areas
- Oncology
- Cancer Research