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

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3340 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 [1M tegafur, 0.4M CDHP and 1M Oxo] and capecitabine) on human colorectal cancer xenografts and evaluated their anti-angiogenic effects. S-1 and capecitabine showed significant antitumor activities against COL-1 xenografts at a semi-toxic dose that was lower than the maximum tolerated dose (S-1: 6.9 mg/kg/day, capecitabine: 360 mg/kg/day). At this dose, a trend towards a reduction in the microvessel number after the administration of 5-FU-based drugs and the enhancement of tumor-associated microvessel endothelial cell apoptosis was seen in xenograft treated with S-1 (P = 0.014). In addition, we found that thrombospondin-1 (TSP-1) mRNA, known to be a mediator of the antiangiogenic effects of metronomic chemotherapy, was significantly up-regulated in xenograft tumor tissues treated with S-1 at a semi-toxic dose (P = 0.006). This induction was reflected at the protein level in tumor tissues and blood plasma. Capecitabine also showed a trend toward the induction of TSP-1 (mRNA: P = 0.079, protein: P = 0.059). 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.