Antitumor effect of TNP-470, an angiogenesis inhibitor, combined with ultrasound irradiation for human uterine sarcoma xenografts evaluated using contrast color Doppler ultrasound

Microvascular endothelial cells, which are recruited by tumors, have become an important target in cancer therapy. This study firstly examined the antitumor effect of angiogenesis inhibitor combined with ultrasound (US) irradiation for human cancer in vivo and evaluated its vascularity using color Doppler US in real time with a microbubble US contrast agent. A human uterine sarcoma cell line, FU-MMT-1, was used in vivo because this tumor is one of the most malignant neoplasms of the human solid tumors and it also has a poor response to any of the chemotherapeutic agents currently used, as well as to radiotherapy. In angiogenic inhibitors, TNP-470 was selected to use in an in vivo study, because this agent showed a higher inhibitory effect in tube formation assay in vitro, than that of FR118487, or thalidomide. The FU-MMT-1 xenografts in nude mice were treated using US at a low-intensity (2.0 w/cm(2), 1MHZ) for 4 min three times per week each after the subcutaneous injection of TNP-470 (30 mg/kg), an angiogenesis inhibitor, and this treatment was continued for 8 weeks. Either treatment of US alone or TNP-470 alone showed a suppression of tumor growth, in comparison to the non-treatment group (control), and a significantly enhanced effect was obtained using the combined treatment. A reduction in the intratumoral vascularity, which was evaluated using both color Doppler and immunohistochemistry, was significantly demonstrated using the combined treatment, in comparison to each treatment alone, and the control. No side-effect was observed in any mice in the combined treatment group. These results suggest that the antitumor effect of TNP-470 for uterine sarcoma was accelerated by US irradiation in vivo and this combination might be a potentially effective for new cancer therapy.