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 (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.
Hama
Y
Y
Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
Shimizu
T
T
Hosaka
S
S
Sugenoya
A
A
Usuda
N
N
D000368:Aged; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D002277:Carcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000627:therapeutic use; D003510:Cyclohexanes; D004317:Doxorubicin / Q000627:therapeutic use; D005169:Factor VIII / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D012717:Sesquiterpenes; D004317:Doxorubicin; D005169:Factor VIII; D002945:Cisplatin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol