o-(chloroacetylcarbamoyl)fumagillol and Thyroid-Neoplasms

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor-induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Carcinoma; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Cell Surface Extensions; Cyclohexanes; Cytoskeleton; Cytotoxicity, Immunologic; Disease Models, Animal; Endothelial Cells; Enzyme Activation; Gap Junctions; Humans; Male; Mice; Mice, Nude; Neoplasm Metastasis; O-(Chloroacetylcarbamoyl)fumagillol; rac GTP-Binding Proteins; Sesquiterpenes; Survival Analysis; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

TNP-470 (AGM-1470), a synthetic analog of fumagillin (6-chloroacetyl-carbamoyloxy-4-(1,2-epoxy-1,5-dimethyl- 4-hexenyl)-5-methoxy-1-oxaspiro [2,5] octane 1, has been reported to reduce the supply of nutrients to experimental tumors by inhibiting angiogenesis. In this study, we investigated anti-tumor activity of TNP-470 against human thyroid anaplastic carcinoma with a view to developing 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 non-functional in excretory hormones and to preserve morphological characteristics of the 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 carcinoma by different routes of administration: intratumoral, peritumoral, subcutaneous and intraperitoneal. Intratumoral and peritumoral administration were effective, and especially the TNP-470 administered by the former route completely inhibited tumor growth. Immunohistochemical analysis using anti-factor VIII antibody revealed the density of microvessels to be significantly decreased by local administration of TNP-470 (intratumoral administration, 7.8 +/- 2.9/mm2, control, 27.0 +/- 6.3/mm2; peritumoral administration, 9.7 +/- 2.6/mm2, control, 21.1 +/- 5.1/mm2). Our findings suggested the possibility of clinical application of TNP-470 to control the growth of human anaplastic thyroid carcinoma.

Topics: Aged; Animals; Antibiotics, Antineoplastic; Carcinoma; Cisplatin; Cyclohexanes; Doxorubicin; Factor VIII; Female; Humans; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Thyroid Neoplasms