o-(chloroacetylcarbamoyl)fumagillol and Carcinosarcoma

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.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinosarcoma; Cell Line, Tumor; Cyclohexanes; Endothelial Cells; Female; Floxuridine; Humans; Mice; Mice, Inbred BALB C; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Thrombospondin 1; Thymidine Phosphorylase; Uterine Neoplasms; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

We assessed the usefulness of Jun N-terminal kinase inhibitor (JNK-I) as an anti-angiogenic agent against a human uterine carcinosarcoma cell line (FU-MMT-1). JNK-I blocked FU-MMT-1-induced human arterial endothelial cell (HAEC) tube formation in an in vitro co-culture model. Cell proliferation of FU-MMT-1 or HAEC was inhibited by JNK-I. In addition, JNK-I blocked matrix metalloproteinase production but not vascular endothelial growth factor (VEGF) secretion in HAECs. Although low concentrations of JNK-I or TNP-470, an anti-cancer agent, did not separately block FU-MMT-1-induced tube formation, such tube formation was blocked by the combination of low concentrations of JNK-I and TNP-470 because TNP-470 blocked VEGF production, suggesting that JNK-I and TNP-470 had a synergistic effect and might be effective in patients with carcinosarcoma.

Topics: Angiogenesis Inhibitors; Carcinosarcoma; Cell Proliferation; Cyclohexanes; Drug Synergism; Female; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase Kinases; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured; Uterine Neoplasms; Vascular Endothelial Growth Factor A

We evaluated the usefulness of TNP-470 as an anti-cancer agent on a human uterine carcinosarcoma cell line (FU-MMT-1). FU-MMT-1 induced human arterial endothelial cell (HAEC) tube formation on an in vitro co-cultured model of FU-MMT-1 and HAECs on a matrix gel, and was blocked by vascular endothelial growth factor (VEGF)-2 receptor (KDR/Flk-1) tyrosine kinase inhibitor. Lower concentration of TNP-470 inhibited the tube formation. Cell proliferation of FU-MMT-1 but not HAEC was inhibited by lower concentration of TNP-470. In addition, lower concentration of TNP-470 blocked VEGF production on FU-MMT-1. Our results suggest that TNP-470 directly inhibited FU-MMT-1 but not HAEC growth accompanied with the inhibition of VEGF production, subsequently induced anti-angiogenesis on HAEC.

Topics: Angiogenesis Inhibitors; Carcinosarcoma; Cell Division; Cyclohexanes; Endothelium, Vascular; Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured; Vascular Endothelial Growth Factor Receptor-2

Carcinosarcoma is the most aggressive neoplasm of among the known uterine malignancies. Most tumors show lymph-vascular space invasion and are clinically resistant to any chemotherapeutic drug currently used as well as any radiotherapy. This is the first study to investigate a novel therapeutic approach using an angiogenesis inhibitor TNP-470, a synthetic analogue of fumagillin, for human uterine carcinosarcoma in vivo.. The growth-inhibitory and anti-angiogenic effects of TNP-470 were examined after inoculating a human uterine carcinosarcoma cell line, FU-MMT-1, in nude mice. Intratumoral blood flow was evaluated weekly by color Doppler ultrasound (CDU) after the xenografts measurably developed during the period of treatment. The microvessel density (MVD) in TNP-470-treated xenografts was also immunohistochemically examined.. TNP-470 significantly reduced the volume as well as the weight of the xenografts when this therapy was started 3 weeks (Day 21) after the inoculation of FU-MMT-1, in comparison to the controls. Neither weight loss nor ataxia was observed in any mice of this therapy. A main feeding artery for the xenograft was detected by CDU in all mice treated in this study. However, no significant difference in either the vessel density visualized by CDU or MVD between the TNP-470-treated xenografts and controls was observed.. These results suggest that TNP-470 may inhibit the growth of human uterine carcinosarcoma in vivo. We speculate that TNP-470 may be a useful agent for adjuvant therapy in patients with advanced or recurrent uterine carcinosarcomas. However, a further evaluation in molecular level of the anti-angiogenic effect of TNP-470 against this tumor in vivo is thus called for.

Topics: Angiogenesis Inhibitors; Animals; Antibiotics, Antineoplastic; Carcinosarcoma; Cell Division; Cyclohexanes; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tumor Cells, Cultured; Uterine Neoplasms; Xenograft Model Antitumor Assays