Suppression of tumor growth and downregulation of platelet-derived endothelial cell growth factor / thymidine phosphorylase in tumor cells by angiogenesis inhibitor TNP-470.
We investigated the effects of the angiogenesis inhibitor TNP-470 on human lung squamous cell carcinoma cell lines H226B and H226Br both in vivo and in vitro. H226B was established from human lung squamous cell carcinoma and H226Br was established from a brain metastatic lesion of H226B in nude mice. Nude mice inoculated with these cells were treated with 30 mg / kg of TNP-470 subcutaneously every other day. At this dose, TNP-470 only significantly suppressed the growth of H226Br tumor, but not H226B tumor. Attempts to use a high dose of TNP-470 (100 mg / kg) resulted in a severe loss of body weight. Immunohistochemical studies showed marked tumor vascularization in H226Br tumor, but the formation of new blood vessels was suppressed by 30 mg / kg of TNP-470. Investigation of the mechanism of anti-angiogenic effects of TNP-470 in vivo showed that the expression and the activity of platelet-derived endothelial cell growth factor / thymidine phosphorylase (PD-ECGF / dThdPase) in H226Br tumor was significantly suppressed by 30 mg / kg of TNP-470. Furthermore, TNP-470 inhibited cell growth of cultured H226Br dose-dependently at concentrations of 1 microg / ml. Immunoblot analysis revealed H226Br cells gave a stronger PD-ECGF signal than H226B cells, and the expression of PD-ECGF / dThdPase in H226Br was also suppressed by treatment with TNP-470 at 0.1 microg / ml. No change in basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) was noted in these cell lines. Our results suggested that TNP-470 acts, at least in part, by downregulation of PD-ECGF / dThdPase in this cell line.
Mori
J
J
First Department of Surgery, Okayama University Medical School, Okayama City 700-8558, Japan.
Haisa
M
M
Naomoto
Y
Y
Takaoka
M
M
Kimura
M
M
Yamatsuji
T
T
Notohara
K
K
Tanaka
N
N
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*; D013939:Thymidine Phosphorylase / Q000096:biosynthesis* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D006131:Growth Inhibitors; D012717:Sesquiterpenes; D013939:Thymidine Phosphorylase; D000077609:O-(Chloroacetylcarbamoyl)fumagillol