title: Docetaxel enhances the therapeutic effect of the angiogenesis inhibitor TNP-470 (AGM-1470) in metastatic human transitional cell carcinoma.
abstract: We demonstrated recently that chronic frequent administration of an adequate biological dose of the angiogenesis inhibitor TNP-470 (AGM-1470, O-chloracetyl-carbamoyl fumagillol) completely inhibits spontaneous lymph node metastasis but does not have a complete response on tumor growth of nonestablished or established human metastatic transitional cell carcinoma (TCC) 253J B-V growing orthotopically into athymic nude mice. Therefore, in this study, we evaluated whether docetaxel (Taxotere) enhances the therapeutic effect of TNP-470, especially on tumor growth. Docetaxel enhanced in vitro antiproliferation but not basic fibroblast growth factor down-regulation by TNP-470 in 253J B-V and human umbilical vascular endothelial cells. Docetaxel significantly enhanced in vitro apoptosis by TNP-470 in human umbilical vascular endothelial cells but not in 253J B-V. In vivo combination was most effective when docetaxel was administered before TNP-470, and increased significantly the complete response on tumor growth of nonestablished and established TCCs growing orthotopically into athymic nude mice compared with either therapy alone (P < 0.05). The incidence of spontaneous lymph node metastasis was inhibited completely by the combination therapy (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment groups. The combination of TNP-470 and docetaxel inhibited intratumor neovascularization, the expression of bFGF and matrix metalloproteinases type-9 compared with controls (P < 0.005), and enhanced apoptosis in tumors compared with each therapy alone (P < 0.005). These studies indicate that docetaxel markedly enhances the ability of TNP-470 to inhibit tumorigenicity and metastasis in both nonestablished and established TCCs. These effects are mediated, in part, by the complementary cytotoxicities of angiogenesis inhibition, down-regulation of bFGF and matrix metalloproteinases type-9, and induction of apoptosis.
authors.affiliation: Department of Urology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Inoue
authors.forename: Masakazu
authors.initials: M
authors.lastname: Chikazawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukata
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yoshikawa
authors.forename: Taro
authors.initials: T
authors.lastname: Shuin
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D003510:Cyclohexanes; D000077143:Docetaxel; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D012717:Sesquiterpenes / Q000627:therapeutic use*; D043823:Taxoids; D013997:Time Factors; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel; D000077609:O-(Chloroacetylcarbamoyl)fumagillol