o-(chloroacetylcarbamoyl)fumagillol and Endometrial-Neoplasms

To know the potential of growth, invasion and metastasis of endometrial cancer associated with neovascularization, the effects of sex steroids and O-(chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM-1470) on basic fibroblast growth factor (FGF) expression and secretion and its mRNA expression were investigated in well-differentiated endometrial cancer cell line Ishikawa and in undifferentiated endometrial cancer cell line AN3 CA. Basic FGF expression and secretion and its mRNA expression in Ishikawa cells, but not in AN3 CA cells, were increased by estrogen, while progesterone diminished the estrogen-induced increases. TNP-470 reduced the levels regardless of estrogen treatment in AN3 CA cells. Therefore, basic FGF secretion may be inhibited by progestin in differentiated cells, and by TNP-470 in undifferentiated cells. Since endometrial cancer consists of differentiated and undifferentiated cells as heterogeneity, a combination therapy for endometrial cancer with progestin and TNP470 might be effective.

Topics: Antibiotics, Antineoplastic; Blotting, Southern; Cyclohexanes; Dose-Response Relationship, Drug; Endometrial Neoplasms; Estradiol; Female; Fibroblast Growth Factor 2; Humans; O-(Chloroacetylcarbamoyl)fumagillol; Polymerase Chain Reaction; Progesterone; RNA, Messenger; Sesquiterpenes; Tumor Cells, Cultured

Antitumor activity of angiogenesis inhibitor TNP-470 was evaluated in eight human cultured cell lines derived from choriocarcinoma: SCH, NUC-1, and GCH-1(m); ovarian cancer; TYK and Nakajima; and uterine endometrial cancer: HEC-6, HEC-50, and HEC-1-A. After 7-day culture with TNP-470, in medium at the concentration of 10(1) to 10(-2) micrograms/ml, the inhibition of growth was observed in all of the eight cell lines. The 50% inhibitory concentration of choriocarcinona cell lines was at an extremely low level compared to that of epithelial ovarian cancer and uterine endometrial cancer. In addition, the antitumor effect of this compound was studied in in vivo experiments using nude mice with tumors of GCH-1(m), NUC-1, or Nakajima cells. When the size of the transplanted tumor reached 100-200 mm3 in volume, 3, 10, or 30 mg/kg of TNP-470 was injected s.c. every other day. The inhibitory effect of TNP-470 was obtained by the administration of 10 and 30 mg/kg in GCH-1(m) and NUC-1 cells, respectively, while in Nakajima cells no significant effect was observed. In nude mice treated with 30 mg/kg of TNP-470, lung metastasis of GCH-1(m) cells was strongly inhibited both in the number and in the size of tumor nodules, indicating that the capillary growth in the originally developed tumor was also significantly reduced. These results suggest that the clinical setting using TNP-470 may be one of the promising treatments for the metastasis of tumor cells.

Topics: Animals; Cell Division; Choriocarcinoma; Cyclohexanes; Drug Screening Assays, Antitumor; Endometrial Neoplasms; Female; Humans; In Vitro Techniques; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Metastasis; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Ovarian Neoplasms; Sesquiterpenes; Tumor Cells, Cultured