Evaluation of in vitro cytotoxicity of nonsteroidal anti-inflammatory drugs against canine tumor cells

Deborah W. Knapp From the Departments of Veterinary Clinical Sciences (Knapp), Veterinary Physiology and Pharmacology (Chan, Park), Statistics (Kuczek), and Veterinary Pathobiology (Reagan), Purdue University, West Lafayette, IN 47907.

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Thomas C. K. Chan From the Departments of Veterinary Clinical Sciences (Knapp), Veterinary Physiology and Pharmacology (Chan, Park), Statistics (Kuczek), and Veterinary Pathobiology (Reagan), Purdue University, West Lafayette, IN 47907.

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Thomas Kuczek From the Departments of Veterinary Clinical Sciences (Knapp), Veterinary Physiology and Pharmacology (Chan, Park), Statistics (Kuczek), and Veterinary Pathobiology (Reagan), Purdue University, West Lafayette, IN 47907.

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William J. Reagan From the Departments of Veterinary Clinical Sciences (Knapp), Veterinary Physiology and Pharmacology (Chan, Park), Statistics (Kuczek), and Veterinary Pathobiology (Reagan), Purdue University, West Lafayette, IN 47907.

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Beth Park From the Departments of Veterinary Clinical Sciences (Knapp), Veterinary Physiology and Pharmacology (Chan, Park), Statistics (Kuczek), and Veterinary Pathobiology (Reagan), Purdue University, West Lafayette, IN 47907.

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SUMMARY

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 (lC50) against melanoma cells in short-term growth rate assays were: 530 μM piroxicam, 180 μM 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 μM) was not different from the IC50 of zileuton alone (230 μM; anova P = 0.47) in melanoma cells. Similarly, addition of piroxicam did not alter the IC50 of either cisplatin (1.6 μM) or carboplatin (6.1 μM). 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.

SUMMARY

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 (lC50) against melanoma cells in short-term growth rate assays were: 530 μM piroxicam, 180 μM 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 μM) was not different from the IC50 of zileuton alone (230 μM; anova P = 0.47) in melanoma cells. Similarly, addition of piroxicam did not alter the IC50 of either cisplatin (1.6 μM) or carboplatin (6.1 μM). 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.

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