ANTITUMOR-ACTIVITY OF A MEDIUM-CHAIN TRIGLYCERIDE SOLUTION OF THE ANGIOGENESIS INHIBITOR TNP-470 (AGM-1470) WHEN ADMINISTERED VIA THE HEPATIC-ARTERY TO RATS BEARING WALKER-256 CARCINOSARCOMA IN THE LIVER

The antitumor effect of an angiogenesis inhibitor, TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), administered via the hepati c artery in a medium-chain triglyceride (MCT) solution, in which TNP-4 70 is very stable, was examined in rats bearing Walker 256 carcinosarc oma in the liver. The MCT solution containing 0.1 mg of TNP-470 comple tely suppressed tumor growth after a single arterial injection, and th e solutions containing 0.5 similar to 5 mg of TNP-470 caused tumor reg ression without severe side effects on body weight gain or liver funct ion. These antitumor effects lasted for at least 2 weeks. Moreover, th e administration of the MCT solution containing 5 mg of TNP-470 also c aused remarkable regression of well-developed enlarged tumors 2 weeks after inoculation, indicating potential in the treatment of unresectab le hepatic cancer. When the MCT solution containing radiolabeled TNP-4 70 was injected via the hepatic artery, the initial radioactivity in t he tumor was 22 times that in the normal part of the liver and 5.7 tim es 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 wee ks after injection. These results indicate that the remarkable antitum or effect resulted from the selective delivery and prolonged retention of TNP-470 at the tumor site.