The role of thymidine phosphorylase, an angiogenic enzyme, in tumor progression.
Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). TP is overexpressed in various tumors and plays an important role in angiogenesis, tumor growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP. A novel, specific TP inhibitor, TPI, inhibits angiogenesis induced by overexpression of TP in KB/TP cells (human KB epidermoid carcinoma cells transfected with TP cDNA), as well as the growth and metastasis of KB/TP cells in vivo. 2-deoxy-D-ribose, the degradation product of thymidine generated by TP activity, has both angiogenic and chemotactic activity. Both 2-deoxy-D-ribose and TP inhibit a hypoxia-induced apoptotic pathway. These findings suggest that 2-deoxy-D-ribose is a downstream mediator of TP function. 2-deoxy-L-ribose, a stereoisomer of 2-deoxy-D-ribose, inhibits the promotion of angiogenesis, tumor growth and metastasis by TP. Although the mechanism of the action of 2-deoxy-D-ribose is still unknown, 2-deoxy-L-ribose may inhibit the physiological activities of 2-deoxy-D-ribose, and consequently those of TP. Inhibition of TP activity and function appears to be a promising approach for the chemotherapy of various tumors.
Akiyama
Shin-ichi
S
Department of Molecular Oncology, Course of Advanced Therapeutics, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544. akiyamas@m3.kufm.kagoshima-u.ac.jp
Furukawa
Tatsuhiko
T
Sumizawa
Tomoyuki
T
Takebayashi
Yuji
Y
Nakajima
Yuichi
Y
Shimaoka
Shunji
S
Haraguchi
Misako
M
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003855:Deoxyribose / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D013936:Thymidine / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000502:physiology*; D000097382:CD68 Molecule
D043925:Angiogenesis Inducing Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D003855:Deoxyribose; D013936:Thymidine; D013939:Thymidine Phosphorylase; C067980:CD68 antigen, human; D000097382:CD68 Molecule