Suppression of metastasis by thymidine phosphorylase inhibitor.
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 beta-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.
Takao
S
S
First Department of Surgery Kagoshima University School of Medicine, Sakuragaoka, Japan. sonshin@med6.kufm.kagoshima-u.ac.jp
Akiyama
S I
SI
Nakajo
A
A
Yoh
H
H
Kitazono
M
M
Natsugoe
S
S
Miyadera
K
K
Fukushima
M
M
Yamada
Y
Y
Aikou
T
T
D000818:Animals; D001485:Basement Membrane / Q000187:drug effects / Q000473:pathology; D001609:Beta-Globulins / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007624:KB Cells; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011759:Pyrrolidines / Q000494:pharmacology* / Q000633:toxicity; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity
C119063:5-chloro-6-(1-(2-iminopyrrolidinyl) methyl)uracil hydrochloride; D001609:Beta-Globulins; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D014498:Uracil; D013939:Thymidine Phosphorylase