Cancer Lett. 2008 Aug 18;267(1):26-36. Epub 2008 Apr 16.
Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts.Ooyama A, Oka T, Zhao HY, Yamamoto M, Akiyama S, Fukushima M.Personalized
Medicine Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2
Ebisuno, Hiraishi, Tokushima 771-0194, Japan.
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 5-chloro-2,4-dihydroxypyridine and 1M 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.