o-(chloroacetylcarbamoyl)fumagillol and Tongue-Neoplasms

We examined the three-dimensional changes of the lymphatic architecture in the rabbit VX2 tongue cancer model after administration of an antiangiogenic agent, TNP-470. TNP-470 at 30 mg/kg was administered via the auricular vein to the rabbit four times every other day from 3 days after transplantation of the tumor. The tongue and both sides of deep cervical lymph nodes of rabbit were observed at 10 days after transplantation. Lymph node metastasis was confirmed histopathologically. Morphological changes of collecting lymphatic vessels and lymphatic capillaries were observed, and the number and diameter of lymphatic vessels within 500 microm around the tumor were measured using the combined method with 5'-nucleotidase staining and three-dimensional reconstruction imaging. Tumor growth and lymph node metastasis were suppressed by administration of TNP-470. In the TNP-treatment group, the mean number of lymphatic capillaries was significantly fewer than in the control group. The mean diameter of collecting lymphatic vessels was significantly smaller than in the control group. In conclusion, our results suggest that cancer cell invasion into the lymphatics is probably decreased by inhibiting not only the growth of tumor but also new formation of lymphatic capillaries around the tumor by administration of TNP-470.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Cyclohexanes; Disease Models, Animal; Imaging, Three-Dimensional; Lymph Nodes; Lymphatic Metastasis; Lymphatic System; Lymphatic Vessels; Male; Neoplasm Transplantation; O-(Chloroacetylcarbamoyl)fumagillol; Rabbits; Sesquiterpenes; Tongue Neoplasms

Clinical and histopathological results in human tumors indicate that the connection of solid tumors to the vascular system precedes the exponential tumor growth and further progression. Acknowledging the concept of tumor angiogenesis, the search for angiogenesis inhibiting agents as potential drugs in cancer treatment began rather early. In the present preclinical nude mice model, the antitumoral effect of TNP-470 on xenotransplanted squamous cell carcinoma was tested. The chosen dosage of 30 mg/kg and 60 mg/kg resulted in a significant growth inhibition (P = 0.006 and P = 0.01) compared to the control group. The available in vivo and in vitro data lead to the conclusion that the concept of angiogenesis inhibition will have some impact on treatment of solid tumors in the near future.

Topics: Angiogenesis Inhibitors; Animals; Carcinoma, Squamous Cell; Cyclohexanes; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tongue Neoplasms; Tumor Cells, Cultured

A semi-synthetic analogue of fumagillin, TNP-470, has been shown to be a potent angiogenesis inhibitor. In this study, we evaluated the anti-tumor efficacy of TNP-470 on rabbits bearing VX2 carcinoma of the tongue, by comparison of topical, intra-tumor (i.t.) injection with systemic, intra-venous (i.v.) administration. The i.t. injection of the angiogenesis inhibitor produced much stronger anti-tumor effects, and almost complete tumor regression was achieved at doses of 10 mg/kg or 20 mg/kg. TNP-470 injected intra-tumorally significantly reduced expression of proliferating cell nuclear antigen (PCNA) and microvessel density in the VX2 carcinoma of the tongue. TNP-470 also halted the tumor-associated neovascularization in the rabbit cornea assay. These data suggest that i.t. injection of TNP-470 effectively inhibits tumor angiogenesis and disrupts microvasculature development, which may suppress tumor growth. In conclusion, the i.t. injection of TNP-470 provided remarkable anti-tumor effects on the VX2 carcinoma of the tongue and is expected to have promising therapeutic uses for oral cancer.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma; Corneal Diseases; Cyclohexanes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Eye Neoplasms; Injections, Intralesional; Male; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rabbits; Sesquiterpenes; Time Factors; Tongue Neoplasms

Topics: Animals; Antibiotics, Antineoplastic; Chemotherapy, Cancer, Regional Perfusion; Cyclohexanes; Infusions, Intravenous; Lymphatic Metastasis; Male; O-(Chloroacetylcarbamoyl)fumagillol; Rabbits; Sesquiterpenes; Tongue Neoplasms