title: Metronomic doxifluridine chemotherapy combined with the anti-angiogenic agent TNP-470 inhibits the growth of human uterine carcinosarcoma xenografts.
abstract: Uterine carcinosarcoma is a highly aggressive gynecological neoplasm that responds poorly to conventional chemotherapy and radiotherapy. Metronomic chemotherapy is accepted as a new approach for cancer treatment, and its underlying mechanism seems to involve the suppression of angiogenesis. However, the efficacy of metronomic and anti-angiogenic therapies against uterine carcinosarcoma is unknown. The anti-angiogenic effect of doxifluridine was assessed in vitro using human umbilical vein endothelial cells (HUVEC) co-cultured with FU-MMT-1 human uterine carcinosarcoma cells. The antitumor and anti-angiogenic effects of metronomic doxifluridine (delivered via oral gavage) in combination with TNP-470 were evaluated in vivo. Tumor vascularity was assessed by contrast-enhanced color Doppler ultrasound, laser Doppler and microvessel density staining. Doxifluridine suppressed tube formation of HUVEC and vascular endothelial growth factor production by FU-MMT-1 cells. Metronomic doxifluridine alone significantly suppressed tumor growth compared with the untreated (control) group, while metronomic doxifluridine in combination with TNP-470 significantly inhibited tumor growth compared with each treatment alone. A significant reduction of intratumoral vascularity was observed in FU-MMT-1 xenografts following treatment with metronomic doxifluridine in combination with TNP-470, as compared with each treatment alone. Intestinal bleeding was only observed when the maximum tolerated dose of doxifluridine was administered in combination with TNP-470. Metronomic doxifluridine chemotherapy in combination with TNP-470 might be effective for uterine carcinosarcoma without marked toxicity, possibly acting via its potent anti-angiogenic effects. Clinical studies are needed to evaluate the safety and efficacy of this treatment in humans.
authors.affiliation: Department of Obstetrics and Gynecology, Fukuoka University, Fukuoka, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Naganuma
authors.forename: Batsuren
authors.initials: B
authors.lastname: Choijamts
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shirota
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakajima
authors.forename: Shigenori
authors.initials: S
authors.lastname: Ogata
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kawarabayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Emoto
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002296:Carcinosarcoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003510:Cyclohexanes / Q000008:administration & dosage*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000008:administration & dosage*; D019700:Thrombospondin 1 / Q000235:genetics; D013939:Thymidine Phosphorylase / Q000032:analysis; D014594:Uterine Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D005467:Floxuridine; D013939:Thymidine Phosphorylase; C025034:doxifluridine; D000077609:O-(Chloroacetylcarbamoyl)fumagillol