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MAP, a combination of 6-AN, 6-MMPR, and PALA, is a potential therapeutic anticancer regimen that depletes tumoral ATP and increases tumor regression. A toxicity study was conducted using Beagle dogs to identify target organs and its reversibility. Male and female dogs were administered a single iv dose of 6-AN (6-aminonicotinamide), 6-MMPR (methylmercaptopurineriboside), and PALA (L-aspartic acid-N-phosphonoacetyl disodiumsalt). Two dogs/sex/group were given vehicle or PALA on Day 1 and vehicle and/or 6-MMPR and/or 6-AN on Day 2 to reflect the intended clinical protocol. PALA (12.5 mg/kg) and 6-MMPR (7.5 mg/kg) dosages were kept constant, whereas the 6-AN dose varied. By group, the dosing regimen was vehicle only (Group 1); PALA/6-MMPR (Group 2); 6-AN only (Group 3); and PALA/6-MMPR with 6-AN (0.25, 0.75, and 1.5 mg/kg; Groups 4, 5, and 6, respectively). Necropsies were performed on Days 8 and 33 (1 dog/sex/group/necropsy day). There were no changes in clinical observations or body weights that were attributed to any of the test articles. Mild, reversible increases in ALP, AST, ALT, and/or GGT on Days 5 and/or 8, indicated the presence of hepatocellular alteration (increased transaminases), stress (increased ALPs), and cholestasis (increased ALP and GGT). These results were most likely due to PALA and/or 6-MMPR, since all of the affected groups received both of these test articles with or without 6-AN and Group 3, which did not exhibit these enzyme changes, received only 6-AN. Terminal body weight and gross and microscopic pathology results did not indicate any evidence of drug-related toxicity. Increased ALP, ALT, AST, and GGT noted in some dogs given PALA and 6-MMPR indicated hepatocellular alteration and cholestasis, but no microscopic pathology correlates could be found for these biochemical changes. Based on the clinical pathology findings, the liver was considered a target organ. The no-observable-adverse-effect level (NOAEL) is less than 12.5 mg/kg for PALA in combination with 7.5 mg/kg for 6-MMPR when administered with or without 6-AN. The NOAEL for 6-AN is greater than 1.5 mg/kg since no signs of toxicity were seen when administered alone or in combination with PALA and 6-MMPR (supported by NCI Contract N01-CM-42200 under the NCI RAID Program).

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA