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


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


METHODS
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
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 tumor-bearing dogs.
Marr
Amanda K
AK
Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
Kurzman
Ilene D
ID
Vail
David M
DM
D000818:Animals; D001774:Blood Chemical Analysis / Q000662:veterinary; D001824:Body Constitution / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology*; D004285:Dogs / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000662:veterinary*; D006403:Hematologic Tests / Q000662:veterinary; D008081:Liposomes; D020714:Maximum Tolerated Dose; D016482:Urinalysis / Q000662:veterinary
D008081:Liposomes; D002945:Cisplatin