o-(chloroacetylcarbamoyl)fumagillol and Carcinoma-256--Walker

The antiangiogenic effects of TNP-470 on the neovascularization of tumors were studied by examining ultrastructural alterations in the vasculature and interstitial fluid pressure (IFP) of tumors. Wistar rats were first inoculated subcutaneously (s.c.) with the Walker 256 carcinosarcoma cell line, then either vehicle medium or TNP-470, 30 mg/kg, was injected s.c. on day 1. A tumor growth assay, the necrotic area, and the IFP in the tumor were all measured on day 12. The antiangiogenic effects of TNP-470 were studied by scanning electron microscopic images of tumor vascular casts. TNP-470 was observed to inhibit tumor growth and increase the necrotic area significantly. In the TNP-470-treated group, the IFP in the superficial layer, defined as 2-3 mm from the tumor capsule, and in the deep layer, defined as 8-10 mm from the tumor capsule, were significantly higher than the corresponding values in the control. Moreover, vascular casts showed a significant reduction in the budding of sprouts in the superficial layer, and a decrease in the maximum diameter of the tumor vessels in the deep layer. It is possible that the higher IFP in the TNP-470-treated tumors might have prevented tumor vessel dilation. The findings of this study demonstrated that TNP-470 inhibited the budding of tumor vessel sprouts, and increased the IFP. These processes seem to act synergistically to suppress tumor angiogenesis.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma 256, Walker; Cell Division; Cyclohexanes; Male; Microcirculation; Microscopy, Electron, Scanning; Neoplasm Transplantation; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Rats, Wistar; Sesquiterpenes; Tumor Cells, Cultured

The antitumor effect of an angiogenesis inhibitor, TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), administered via the hepatic artery in a medium-chain triglyceride (MCT) solution, in which TNP-470 is very stable, was examined in rats bearing Walker 256 carcinosarcoma in the liver. The MCT solution containing 0.1 mg of TNP-470 completely suppressed tumor growth after a single arterial injection, and the solutions containing 0.5 approximately 5 mg of TNP-470 caused tumor regression function. These antitumor effects lasted for at least 2 weeks. Moreover, the administration of the MCT solution containing 5 mg of TNP-470 also caused remarkable regression of well-developed enlarged tumors 2 weeks after inoculation, indicating potential in the treatment of unresectable hepatic cancer. When the MCT solution containing radiolabeled TNP-470 was injected via the hepatic artery, the initial radioactivity in the tumor was 22 times that in the normal part of the liver and 5.7 times that in the tumor when an aqueous solution of radiolabeled TNP-470 was injected. Also, in the case of the MCT solution, the radioactivity in the tumor was maintained at a relatively high level for over 2 weeks after injection. These results indicate that the remarkable antitumor effect resulted from the selective delivery and prolonged retention of TNP-470 at the tumor site.

Topics: Alanine Transaminase; Animals; Antibiotics, Antineoplastic; Aspartate Aminotransferases; Carcinoma 256, Walker; Cyclohexanes; Hepatic Artery; Injections, Intra-Arterial; Liver Neoplasms, Experimental; Male; Neovascularization, Pathologic; O-(Chloroacetylcarbamoyl)fumagillol; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Triglycerides

TNP-470, an analog of fumagillin, is one of the new angiogenesis inhibitors. Five days after an intraperitoneal inoculation of 10(7) cells of Walker 256 carcinosarcoma to SD rats, TNP-470 was injected intraperitoneally in the form of TNP aqueous solution or TNP-oil solution. Mean survival time of rats given TNP-oil solution or TNP aqueous solution was statistically prolonged, compared with that of the control rats. Our results showed that TNP-470 is an effective therapeutic drug for carcinomatous peritonitis.

Topics: Animals; Antibiotics, Antineoplastic; Carcinoma 256, Walker; Cyclohexanes; Infusions, Parenteral; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; O-(Chloroacetylcarbamoyl)fumagillol; Peritonitis; Rats; Sesquiterpenes