THERAPEUTIC EFFICACY OF THE ANGIOGENESIS INHIBITOR O-(CHLOROACETYL-CARBAMOYL) FUMAGILLOL (TNP-470, AGM-1470) FOR HUMAN ANAPLASTIC THYROID-CARCINOMA IN NUDE-MICE

TNP-470 (AGM-1470), a synthetic analog of fumagillin epoxy-1,5-dimethy l-4-hexenyl)-5-methoxy-1-oxaspiro [2,5] octane), has been reported to reduce the supply of nutrients to experimental tumors by inhibiting an giogenesis. In this study, we investigated anti-tumor activity of TNP- 470 against human thyroid anaplastic carcinoma with a view to developi ng a new treatment for this thyroid tumor. A transplantable tumor was established from thyroid anaplastic carcinoma of a 78-year-old woman, as a xenograft in nude mice (BALB/c, nu/nu, male). This transplantable tumor, with chromosomal abnormality was shown to be nan-functional in excretory hormones and to preserve morphological characteristics of t he original anaplastic tumor tissue. TNP-470 was given at a dose of 50 mg/kg b.w. to nude mice transplanted with human thyroid anaplastic ca rcinoma by different routes of administration: intratumoral, peritumor al, subcutaneous and intraperitoneal. Intratumoral and peritumoral adm inistration were effective, and especially the TNP-470 administered by the former route completely inhibited tumor growth. Immunohistochemic al analysis using anti-factor VIII antibody revealed the density of mi crovessels to be significantly decreased by local administration of TN P-470 (intratumoral administration, 7.8 +/- 2.9/mm(2), control, 27.0 /- 6.3/mm(2); peritumoral administration, 9.7 +/- 2.6/mm control, 21.1 +/- 5.1/mml). Our findings suggested the possibility of clinical appl ication of TNP-470 to control the growth of human anaplastic thyroid c arcinoma.