Anti-angiogenic effect of 5-Fluorouracil-based drugs against human colon cancer xenografts.
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 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.
Ooyama
Akio
A
Personalized Medicine Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Tokushima 771-0194, Japan. akio-ooyama@taiho.co.jp
Oka
Toshinori
T
Zhao
Hong-ye
HY
Yamamoto
Masatatsu
M
Akiyama
Shin-ichi
S
Fukushima
Masakazu
M
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069287:Capecitabine; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004338:Drug Combinations; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010094:Oxonic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D005641:Tegafur / Q000494:pharmacology* / Q000627:therapeutic use; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D000069287:Capecitabine; D005472:Fluorouracil