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Biological activity of gemcitabine against canine osteosarcoma cell lines in vitro

Melanie B. McMahonDepartments of Veterinary Clinical Sciences, The Ohio State University, Columbus, OH 43210.

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Misty D. BearVeterinary Biosciences, The Ohio State University, Columbus, OH 43210.

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Samuel K. KulpCollege of Veterinary Medicine; Division of Medicinal Chemistry and PharmACognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210.

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Michael L. PennellDivision of Biostatistics, College of Public Health, The Ohio State University, Columbus, OH 43210.

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Cheryl A. LondonDepartments of Veterinary Clinical Sciences, Veterinary Biosciences, The Ohio State University, Columbus, OH 43210.

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Abstract

Objective—To evaluate in vitro biological activity of gemcitabine, alone and in combination with Pamidronate or carboplatin, against canine osteosarcoma (OSA) cell lines.

Sample Population—In vitro cultures of OSA cell lines OSA8, OSA16, OSA32, and OSA36.

Procedures—Cell lines were treated with gemcitabine alone or in combination with pamidronate or carboplatin. Cell viability was assessed with the water soluble tetrazolium-1 (WST-1) assay, cell cycle distribution was evaluated by means of propidium iodide staining, and apoptosis was assessed by measuring caspase-3/7 activity. Synergy was quantified by use of combination index (CI) analysis.

Results—For all of the cell lines, treatment with gemcitabine induced growth inhibition, cell cycle arrest, and apoptosis. No synergistic or additive activity was identified when OSA cell lines were treated with gemcitabine in combination with pamidronate. However, when OSA cell lines were treated with gemcitabine in combination with carboplatin, a significant decrease in cell viability was observed, compared with treatment with carboplatin alone, and the drug combination was determined to be synergistic on the basis of results of CI analysis. For 3 of the 4 cell lines, this activity was greater when cells were treated with carboplatin prior to gemcitabine rather than with gemcitabine prior to carboplatin.

Conclusions and Clinical Relevance—Gemcitabine exhibited biological activity against canine OSA cell lines in vitro, and a combination of gemcitabine and carboplatin exhibited synergistic activity at biologically relevant concentrations. Findings support future clinical trials of gemcitabine alone or in combination with carboplatin for the treatment of dogs with OSA.

Abstract

Objective—To evaluate in vitro biological activity of gemcitabine, alone and in combination with Pamidronate or carboplatin, against canine osteosarcoma (OSA) cell lines.

Sample Population—In vitro cultures of OSA cell lines OSA8, OSA16, OSA32, and OSA36.

Procedures—Cell lines were treated with gemcitabine alone or in combination with pamidronate or carboplatin. Cell viability was assessed with the water soluble tetrazolium-1 (WST-1) assay, cell cycle distribution was evaluated by means of propidium iodide staining, and apoptosis was assessed by measuring caspase-3/7 activity. Synergy was quantified by use of combination index (CI) analysis.

Results—For all of the cell lines, treatment with gemcitabine induced growth inhibition, cell cycle arrest, and apoptosis. No synergistic or additive activity was identified when OSA cell lines were treated with gemcitabine in combination with pamidronate. However, when OSA cell lines were treated with gemcitabine in combination with carboplatin, a significant decrease in cell viability was observed, compared with treatment with carboplatin alone, and the drug combination was determined to be synergistic on the basis of results of CI analysis. For 3 of the 4 cell lines, this activity was greater when cells were treated with carboplatin prior to gemcitabine rather than with gemcitabine prior to carboplatin.

Conclusions and Clinical Relevance—Gemcitabine exhibited biological activity against canine OSA cell lines in vitro, and a combination of gemcitabine and carboplatin exhibited synergistic activity at biologically relevant concentrations. Findings support future clinical trials of gemcitabine alone or in combination with carboplatin for the treatment of dogs with OSA.

Contributor Notes

Supported by a grant from the American College of Veterinary Internal Medicine Foundation.

Presented in part at the 27th Veterinary Cancer Society Conference, Fort Lauderdale, Fla, November 2007.

Dr. McMahon's present address is Northwest Veterinary Specialists, 16756 SE 82nd Dr, Clackamas, OR 97015.

Address correspondence to Dr. London (london.20@osu.edu).