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Preclinical evaluation of a liposome-encapsulated formulation of cisplatin in clinically normal dogs

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  • 1 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 2 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 3 Department of Comprehensive Cancer Center, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 4 MacEwen Center for Clinical Trials and Translational Research, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 5 Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 6 Department of Comprehensive Cancer Center, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 7 MacEwen Center for Clinical Trials and Translational Research, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706.
  • | 8 Present address is the Animal Cancer Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523-1620.

Abstract

Objective—To determine the acute and short-term adverse effects of a liposome-encapsulated form of cisplatin at increasing dosages of up to twice the known maximally tolerated dose (MTD) of unencapsulated cisplatin in clinically normal dogs.

Animals—4 healthy 2.5-year-old sexually intact female hound-type dogs.

Procedure—4 dosages (70, 100, 125, and 150 mg/m2) were evaluated, and the 4 dogs received a total of 9 infusions (1 to 3 infusions/dog). Dogs were monitored to detect changes in clinical and clinicopathologic status. Evaluations consisting of a physical examination, CBC, serum biochemical analysis, and urinalysis were performed before and 7 and 21 days after each infusion.

Results—Acute anaphylactic-like reactions to liposome- encapsulated cisplatin were common but clinically manageable. Nephrotoxicosis and substantial myelosuppression, toxic effects commonly associated with unencapsulated cisplatin, were not observed in dogs treated with liposome-encapsulated cisplatin at dosages equivalent to twice the known MTD of unencapsulated cisplatin.

Conclusions and Clinical Relevance—Liposome-encapsulated cisplatin can be safely administered to clinically normal dogs at dosages of up to 150 mg/m2 without the need for concurrent hydration protocols. This was a necessary prerequisite to enable phase I clinical trials in dogs with naturally developing cancers that could theoretically benefit from escalation in the dosage of cisplatin. Determination of an MTD, cumulative and long-term toxic effects, and efficacy can now be conducted in the context of phase I trials in tumorbearing dogs. (Am J Vet Res 2004;65:1474–1478)

Abstract

Objective—To determine the acute and short-term adverse effects of a liposome-encapsulated form of cisplatin at increasing dosages of up to twice the known maximally tolerated dose (MTD) of unencapsulated cisplatin in clinically normal dogs.

Animals—4 healthy 2.5-year-old sexually intact female hound-type dogs.

Procedure—4 dosages (70, 100, 125, and 150 mg/m2) were evaluated, and the 4 dogs received a total of 9 infusions (1 to 3 infusions/dog). Dogs were monitored to detect changes in clinical and clinicopathologic status. Evaluations consisting of a physical examination, CBC, serum biochemical analysis, and urinalysis were performed before and 7 and 21 days after each infusion.

Results—Acute anaphylactic-like reactions to liposome- encapsulated cisplatin were common but clinically manageable. Nephrotoxicosis and substantial myelosuppression, toxic effects commonly associated with unencapsulated cisplatin, were not observed in dogs treated with liposome-encapsulated cisplatin at dosages equivalent to twice the known MTD of unencapsulated cisplatin.

Conclusions and Clinical Relevance—Liposome-encapsulated cisplatin can be safely administered to clinically normal dogs at dosages of up to 150 mg/m2 without the need for concurrent hydration protocols. This was a necessary prerequisite to enable phase I clinical trials in dogs with naturally developing cancers that could theoretically benefit from escalation in the dosage of cisplatin. Determination of an MTD, cumulative and long-term toxic effects, and efficacy can now be conducted in the context of phase I trials in tumorbearing dogs. (Am J Vet Res 2004;65:1474–1478)