Open AccessMetronomic doxifluridine chemotherapy combined with the anti‐angiogenic agent TNP‐470 inhibits the growth of human uterine carcinosarcoma xenografts
Author(s) -
Naganuma Yasuko,
Choijamts Batsuren,
Shirota Kyoko,
Nakajima Kyoko,
Ogata Shigenori,
Miyamoto Shingo,
Kawarabayashi Tatsuhiko,
Emoto Makoto
Publication year - 2011
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2011.01998.x
Subject(s) - medicine , angiogenesis , chemotherapy , carcinosarcoma , in vivo , vascular endothelial growth factor , angiogenesis inhibitor , combination therapy , radiation therapy , neovascularization , pharmacology , cancer research , oncology , carcinoma , biology , microbiology and biotechnology , vegf receptors
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. ( Cancer Sci 2011; 102: 1545–1552)