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[Cancer Research 60, 5345-5348, October 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Suppression of Metastasis by Thymidine Phosphorylase Inhibitor1

Sonshin Takao2, Shin-ichi Akiyama, Akihiro Nakajo, Hiroyoshi Yoh, Masaki Kitazono, Shoji Natsugoe, Kazutaka Miyadera, Masakazu Fukushima, Yuji Yamada and Takashi Aikou

First Department of Surgery [S. T., A. N., H. Y., M. K., S. N., T. A.], Department of Cancer Chemotherapy, Institute for Cancer Research [S-i. A.], Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan, and Taiho Pharmaceutical Co., Ltd., [K. M., M. F., Y. Y.] Saitama 357, Japan

We developed a novel inhibitor of thymidine phosphorylase (TP), 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI), that is about 1000-fold more active than 6-amino-5-chlorouracil, one of the most potent TP inhibitors. TPI inhibited the high chemotactic motility and basement membrane invasion of KB/TP cells, a TP-positive clone transfected with Rous sarcoma virus (RSV)/TP, to the levels seen in KB/CV cells, a control clone transfected with RSV. In nude mice, oral administration of TPI suppressed not only macroscopic liver metastases of highly metastatic KB/TP cells but also the level of human ß-globin as a molecular marker of micrometastases in the livers of the mice. These findings demonstrate that TP plays a key role in the invasiveness and metastasis of TP-expressing solid tumors and suggest that TPI might be a novel antimetastatic agent for blood-borne metastasis.




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