Therapeutic efficacy of the angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM-1470) for human anaplastic thyroid carcinoma in nude mice.

Abstract

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.

• Authors: Y Hama, T Shimizu, S Hosaka, A Sugenoya, N Usuda
• Journal: Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (Exp Toxicol Pathol) Vol. 49 Issue 3-4 Pg. 239-47 (Aug 1997) ISSN: 0940-2993 [Print] Germany
• PMID: 9314059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cyclohexanes
• Sesquiterpenes
• Doxorubicin
• Factor VIII
• Cisplatin
• O-(Chloroacetylcarbamoyl)fumagillol

Topics

• Aged
• Animals
• Antibiotics, Antineoplastic (therapeutic use)
• Carcinoma (blood supply, drug therapy, pathology)
• Cisplatin (therapeutic use)
• Cyclohexanes
• Doxorubicin (therapeutic use)
• Factor VIII (analysis)
• Female
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation
• Neovascularization, Pathologic (prevention & control)
• O-(Chloroacetylcarbamoyl)fumagillol
• Sesquiterpenes (therapeutic use)
• Thyroid Neoplasms (blood supply, drug therapy, pathology)