Effect of angiogenesis inhibitor TNP-470 on the growth, blood flow, and microvessel density in xenografts of human uterine carcinosarcoma in nude mice

Abstract

Objective 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. Methods 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. Results 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. Conclusion 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.