title: Evaluation of in vitro cytotoxicity of nonsteroidal anti-inflammatory drugs against canine tumor cells.
abstract: Piroxicam and other nonsteroidal anti-inflammatory drugs (NSAID) have antitumor activity against naturally acquired cancer in dogs and human beings, and against experimentally induced tumors in rodents. We are investigating potential mechanisms of NSAID antitumor activity. The direct cytotoxicity of piroxicam indomethacin, and aspirin against 4 canine tumor cell lines (transitional cell carcinoma, squamous cell carcinoma, melanoma, and soft tissue sarcoma) was determined in short-term growth rate assays and in clonogenic assays. Piroxicam was evaluated alone and in combination with the lipoxygenase inhibitor zileuton, and in combination with the chemotherapeutic agents cisplatin and carboplatin. The 50% inhibitory concentrations (IC50) against melanoma cells in short-term growth rate assays were: 530 microM piroxicam, 180 microM indomethacin, and greater than 1 mM aspirin. These IC50 values were over 10 times greater than serum concentrations of these drugs that could safely be achieved in vivo. The IC50 of zileuton combined with piroxicam (280 microM) was not different from the IC50 of zileuton alone (230 microM; ANOVA P = 0.47) in melanoma cells. Similarly, addition of piroxicam did not alter the IC50 of either cisplatin (1.6 microM) or carboplatin (6.1 microM). These results suggest that NSAID, at serum concentrations achievable in vivo, do not have direct cytotoxicity against canine tumor cells tested. It is unlikely that the in vivo antitumor activity of NSAID is attributable to a direct cytotoxic effect.
authors.affiliation: Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Knapp
authors.forename: T C
authors.initials: TC
authors.lastname: Chan
authors.forename: T
authors.initials: T
authors.lastname: Kuczek
authors.forename: W J
authors.initials: WJ
authors.lastname: Reagan
authors.forename: B
authors.initials: B
authors.lastname: Park
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity*; D001241:Aspirin / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000662:veterinary*; D002295:Carcinoma, Transitional Cell / Q000662:veterinary*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004283:Dog Diseases; D004285:Dogs; D004354:Drug Screening Assays, Antitumor / Q000662:veterinary; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000633:toxicity; D007213:Indomethacin / Q000633:toxicity; D008545:Melanoma / Q000662:veterinary*; D010894:Piroxicam / Q000633:toxicity; D012509:Sarcoma / Q000662:veterinary*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay / Q000662:veterinary
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D010894:Piroxicam; D001241:Aspirin; C063449:zileuton; D006918:Hydroxyurea; D007213:Indomethacin