Novel chemoembolization using calcium‐phosphate ceramic microsphere incorporating TNP‐470, an anti‐angiogenic agent

Abstract

The purpose of the present study was to develop a new method of chemoembolization to improve the therapeutic effectiveness and safety profile of cancer treatment. A chemoembolization approach was designed for human solid tumors using resorbable calcium-phosphate ceramic microspheres loaded with an agent anti-angiogenic to tumor vasculature in vivo. The human uterine sarcoma cell line FU-MMT-3 was used in this study because this tumor is aggressive and also exhibits a poor response to radiotherapy or any chemotherapy currently used. The calciumphosphate ceramic microspheres loaded with TNP-470, an antiangiogenic agent, were injected into FU-MMT-3 xenografts in nude mice three times per week for 8 weeks. The treatment using TNP-470-loaded microspheres suppressed tumor growth, compared to treatment with TNP-470 alone, microspheres alone, and the control. The mean tumor weight after treatment using TNP-470-loaded microspheres was significantly lower than that after treatment with microspheres alone. These ceramic microspheres were remarkably embolized in tumor microvessels as well as in the feeding arteries and a significant reduction of intratumoral vascularity was also demonstrated following treatment with TNP-470-loaded microspheres. Severe loss of body weight was not observed in any mice treated with the TNP-470-loaded microspheres, compared to treatment with TNP-470 alone. These results suggest that targeting tumor vasculature in human uterine sarcoma using calcium-phosphate microspheres might be more effective and safer than the treatment that employs anti-angiogenic agent alone. This new chemoembolization method incorporating an anti-angiogenic agent may contribute to the effective treatment of locally advanced or recurrent solid tumors. (Cancer Sci 2010; 101: 984-990) S arcomas, including carcinosarcomas, are uncommon, but are the most aggressive neoplasms among the known uterine malignancies.(1,2) It is well known that these tumors have poor responses to radiotherapy or any of the chemotherapeutic agents with substantial toxic effects that are currently in use.(1-4)The overall 5-year survival rate in all stages of uterine sarcomas is under 40%, which is significantly lower than that in other uterine cancers.(3) The standard treatments for these tumors, except for the early stages, have not yet been determined; thus, new therapeutic strategies must be immediately investigated. Recent studies, including that of the authors, have shown that rapid growth and early metastasis in these tumors might be associated with high angiogenic properties, in comparison to other uterine malignancies. (4)(5)(6) Radiotherapy is one of the most effective treatments for cancers. For deep-seated cancer, however, external irradiation provides only small doses and often causes damage to healthy tissue. Thus, chemoembolization approaches that use various biomaterials might be effective for treating these solid tumors, including cases that have already received radiotherapy.(7) Many biomaterials are used as substitutes for human ...

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