Evaluation of toxicosis of liposome-encapsulated cis-bis-neodecanoato-trans-R, R-1, 2-diaminocyclohexane platinum (II) in clinically normal cats

Leslie E. Fox From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Katrina Toshach From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Maron Calderwood-Mays From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Abdul R. Khokhar From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Paul Kubilis From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Roman Perez-Soler From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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E. Gregory MacEwen From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610-0126 (Fox, Kubilis); the School of Veterinary Medicine, Purdue University, W Lafayette, IN 47907-1248 (Toshach); Florida Vet Path, 13703 Millhopper Rd, Gainesville, FL 32653 (Calderwood-Mays); the Department of Medical Oncology, MD Anderson Cancer Center, the University of Texas, Houston, TX 77030 (Khokar, Perez-Soler); and the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53705 (MacEwen).

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Abstract

Objective

To determine adverse effects of single and multiple doses of liposome-encapsulated cis-bis-neodecanoato-trans-R, R-1, 2-diaminocyclohexane platinum (II) (L-NDDP) administered IV to healthy adult cats.

Animals

10 healthy adult cats.

Procedure

8 cats were given a single dose of L-NDDP (at rates of 75, 100, 150, or 200 mg/m2), and 2 cats were given liposomal lipid (1,500 mg/m2). Six of the 10 cats were given doses of L-NDDP at the maximum tolerated dosage (100 mg/m2) or a lower dosage (75 mg of L-NDDP/m2) at 21-day intervals, for a total of 4 treatments. Hematologic and serum biochemical analyses, urinalyses, and physical examinations were used to monitor effects of L-NDDP.

Results

All cats had transient pyrexia, lethargy, vomiting (1 to 3 times/24 h), inappetence, and an acute species-specific infusion reaction that was prevented by administration of atropine-diphenhydramine. Dose-limiting toxicosis was evident as a 10- day course of lethargy, intermittent vomiting, and diarrhea. In cats given multiple doses, dose-related thrombocytopenia, cumulative myelosuppression, transient increased hepatic transaminase activity, and mild to moderate hepatic hydropic degeneration and proximal renal tubular lipidosis in excess of lipidosis expected for this species were detected. Bone marrow hypoplasia was detected in some cats that received higher doses (cumulative dosages of 300 or 400 mg of L-NDDP/m2).

Conclusion

Cats can safely be given L-NDDP at potentially therapeutic dosages without inducing renal or pulmonary toxicoses.

Clinical Relevance

Because L-NDDP has better tumoricidal activity than cisplatin (in vivo and in vitro) and is not cross resistant, it may be similarly or more efficacious than cisplatin in humans and dogs. (Am J Vet Res 1999;60:257–263)

Abstract

Objective

To determine adverse effects of single and multiple doses of liposome-encapsulated cis-bis-neodecanoato-trans-R, R-1, 2-diaminocyclohexane platinum (II) (L-NDDP) administered IV to healthy adult cats.

Animals

10 healthy adult cats.

Procedure

8 cats were given a single dose of L-NDDP (at rates of 75, 100, 150, or 200 mg/m2), and 2 cats were given liposomal lipid (1,500 mg/m2). Six of the 10 cats were given doses of L-NDDP at the maximum tolerated dosage (100 mg/m2) or a lower dosage (75 mg of L-NDDP/m2) at 21-day intervals, for a total of 4 treatments. Hematologic and serum biochemical analyses, urinalyses, and physical examinations were used to monitor effects of L-NDDP.

Results

All cats had transient pyrexia, lethargy, vomiting (1 to 3 times/24 h), inappetence, and an acute species-specific infusion reaction that was prevented by administration of atropine-diphenhydramine. Dose-limiting toxicosis was evident as a 10- day course of lethargy, intermittent vomiting, and diarrhea. In cats given multiple doses, dose-related thrombocytopenia, cumulative myelosuppression, transient increased hepatic transaminase activity, and mild to moderate hepatic hydropic degeneration and proximal renal tubular lipidosis in excess of lipidosis expected for this species were detected. Bone marrow hypoplasia was detected in some cats that received higher doses (cumulative dosages of 300 or 400 mg of L-NDDP/m2).

Conclusion

Cats can safely be given L-NDDP at potentially therapeutic dosages without inducing renal or pulmonary toxicoses.

Clinical Relevance

Because L-NDDP has better tumoricidal activity than cisplatin (in vivo and in vitro) and is not cross resistant, it may be similarly or more efficacious than cisplatin in humans and dogs. (Am J Vet Res 1999;60:257–263)

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