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.
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.
Stoeltzing
Oliver
O
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030-4009, USA.
Liu
Wenbiao
W
Reinmuth
Niels
N
Fan
Fan
F
Parry
Graham C
GC
Parikh
Alexander A
AA
McCarty
Marya F
MF
Bucana
Corazon D
CD
Mazar
Andrew P
AP
Ellis
Lee M
LM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage*; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D008113:Liver Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage*
D020533:Angiogenesis Inhibitors; D039081:Integrin alpha5beta1; D009842:Oligopeptides; D005472:Fluorouracil; C404392:acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide