o-(chloroacetylcarbamoyl)fumagillol and Stomach-Neoplasms

TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity. Based on these findings we here examined the antiangiogenic effects of TAC-101. Oral administration of TAC-101 (2-8 mg/kg/day) resulted in a drastic suppression of the AZ-521 cell-induced angiogenesis in a mouse dorsal air sac assay system, compared to the vehicle alone. Immunohistochemical analysis with antibody against the endothelial marker CD31 revealed a significant reduction in microvessel density in liver metastases from animals treated with TAC-101 (8 mg/kg p.o.), compared to liver metastases from the untreated control animals. The ability of TAC-101 (8 mg/kg p.o.) to prevent experimental liver metastasis of AZ-521 cells in athymic nude mice was comparable with that of the known angiogenesis inhibitor TNP-470 (30 mg/kg s.c.). TAC-101 also affected angiogenesis in chorioallantoic membranes and some functions of endothelial cells associated with angiogenesis, whereas the retinoid failed to suppress AZ-521 cell proliferation directly. These data suggest that the TAC-101 is an orally active antiangiogenic agent and that this antiangiogenic property may contribute to its efficacy against liver metastasis of human stomach cancer cells.

Topics: Administration, Oral; Animals; Benzoates; Cell Division; Cell Movement; Cisplatin; Cyclohexanes; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Immunohistochemistry; Liver Neoplasms; Mice; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Platelet Endothelial Cell Adhesion Molecule-1; Sesquiterpenes; Stomach Neoplasms; Trimethylsilyl Compounds; Tumor Cells, Cultured

To study the effect of angiogenesis inhibitor TNP-470 on the growth and metastasis of gastric cancer in vivo.. Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. TNP-470 was administered s.c. at doses of 0 mg/kg, 15 mg/kg, 30 mg/kg, 60 mg/kg every other day for eight weeks. Ten weeks after implantation, the mice were sacrificed and the tumor size measured and the presence of metastasis recorded. The microvascular density was examined by immunohistochemical staining with anti-human factor VIII antibody.. Compared to the untreated controls, growth of the orthotopically implanted tumor was significantly reduced in size in mice treated with TNP-470 with an inhibition rate of 59.9%, 77. 0% and 84.9% at the dosage of 15 mg/kg, 30 mg/kg and 60 mg/kg, respectively. Tumor metastasis to the liver and peritoneaum was also significantly inhibited in a dose-dependent manner. The microvascular density was also decreased significantly in the treated mice.. Angiogenesis inhibitor TNP-470 has strong inhibitory effect both on tumor growth and metastasis of human gastric cancer in nude mice.

Topics: Animals; Antibiotics, Antineoplastic; Cyclohexanes; Female; Humans; Liver Neoplasms; Mice; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peritoneal Neoplasms; Sesquiterpenes; Stomach Neoplasms; Tumor Cells, Cultured

The effect of an angiogenesis inhibitor, TNP-470, on primary tumor growth, liver metastasis and peritoneal dissemination of gastric cancer was investigated by means of an orthotopic xenotransplanted model of 2 human gastric cancers, MT-2 and MT-5. TNP-470 showed a significant inhibitory effect on the growth of primary tumors after orthotopic transplantation of both xenografts when given at a dose of 30 mg/kg on alternate days from day 7 after transplantation (early treatment). However, growth of the MT-2 primary tumor was not inhibited by administration from day 14 after transplantation (late treatment). Liver metastasis was prevented significantly by early treatment of TNP-470. In particular, early treatment of MT-2 completely inhibited the development of macroscopic foci in the liver and was significantly more effective than late treatment. Peritoneal dissemination also was inhibited. Thus, TNP-470 was revealed to have strong inhibitory activity not only on primary tumors and liver metastases but also against peritoneal dissemination. These results suggest that this agent may provide a new approach to the treatment of gastric cancer.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Body Weight; Cell Division; Cyclohexanes; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Peritoneal Neoplasms; Sesquiterpenes; Stomach Neoplasms; Transplantation, Heterologous; Tumor Cells, Cultured

The anti-tumor and anti-metastatic effects of TNP-470, an angiogenesis inhibitor, and mitomycin C (MMC), a representative anti-neoplastic agent, were investigated using our established liver-metastasizing gastric carcinoma line, AZ-H5c. AZ-H5c was injected into the spleen of nude mice which had been randomly divided into 4 groups; a control group given saline solution, a group receiving 15 mg/kg TNP-470, a group receiving 30 mg/kg TNP-470 and a group receiving 2 mg/kg MMC. TNP-470 was given s.c. on alternate days for 5 weeks from day 10 after intrasplenic injection, and MMC was administered intraperitoneally (i.p.) once a week from day 10 after intrasplenic injection. In the control group, liver metastasis developed in 13 of 16 mice (81%). Liver metastasis developed in 6 of 11 mice (55%) receiving MMC. In contrast, liver metastasis developed in 4 of 8 mice (50%) receiving 15 mg/kg TNP-470, and in 0 of 14 mice (0%) receiving 30 mg/kg TNP-470. However, TNP-470 had no effect on the tumor growth. These results indicate that the angiogenesis inhibitor TNP-470 has a strong inhibitory activity against in vivo liver metastasis of human gastric carcinoma.

Topics: Animals; Antibiotics, Antineoplastic; Cell Division; Cyclohexanes; Female; Humans; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitomycin; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Stomach Neoplasms; Tumor Cells, Cultured

Topics: Animals; Antibiotics, Antineoplastic; Combined Modality Therapy; Cyclohexanes; Esophageal Neoplasms; Humans; Hyperthermia, Induced; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Stomach Neoplasms