Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts

• Published in: Cancer letters 2008-08, Vol.267 (1), p.26-36
• Main Authors: Ooyama, Akio, Oka, Toshinori, Zhao, Hong-ye, Yamamoto, Masatatsu, Akiyama, Shin-ichi, Fukushima, Masakazu
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Angiogenesis; Angiogenesis Inhibitors - pharmacology; Animals; Bone marrow; Breast cancer; Cancer therapies; Capecitabine; Chemotherapy; Colonic Neoplasms - drug therapy; Colorectal cancer; Cytotoxicity; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Combinations; Drug dosages; Fluorouracil - analogs & derivatives; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gastric cancer; Hematology, Oncology and Palliative Medicine; Male; Metronomic chemotheraphy; Mice; Mice, Inbred BALB C; Mice, Nude; Oxonic Acid - pharmacology; Oxonic Acid - therapeutic use; Rodents; Tegafur - pharmacology; Tegafur - therapeutic use; Thrombospondin 1 - metabolism; TSP-1; Tumors; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2008.03.008

Abstract In addition to the direct cytotoxic effects of chemotherapy agents on tumor cells, the anti-angiogenic activities attained by these agents by targeting proliferating endothelial cells in tumor blood vessels has attracted much research interest. In this study, we examined the antitumor activity of 5-Fluorouracil (5-FU)-based drugs (S-1 [1 M tegafur, 0.4 M 5-chloro-2,4-dihydroxypyridine and 1 M potassium oxonate] and capecitabine) on human colorectal cancer xenografts and evaluated their anti-angiogenic effects. Both drugs showed significant antitumor activities against COL-1 xenografts at a sub-maximum tolerated dose (sub-MTD), which was lower than the maximum tolerated dose (MTD). At the sub-MTD, a significant reduction in the microvessel number and the enhancement of tumor-associated microvessel endothelial cell apoptosis was seen in xenografts treated with S-1. In addition, we found that thrombospondin-1 (TSP-1) expression, known to be a mediator of the anti-angiogenic effects of metronomic chemotherapy, was significantly up-regulated in xenograft tumor tissues and plasma in animals treated with S-1 at a sub-MTD. Capecitabine also showed a trend toward the induction of TSP-1. These results suggest that 5-FU-based drugs inhibit tumor progression through different modes of action, including cytotoxic activity derived from 5-FU and the inhibition of angiogenesis through the induction of TSP-1.