Phase I clinical trial of the use of zinc phthalocyanine tetrasulfonate as a photosensitizer for photodynamic therapy in dogs

Antonella Borgatti-Jeffreys Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Stephen B. Hooser Department of Comparative Pathobiology, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Margaret A. Miller Department of Comparative Pathobiology, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

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Michael D. Lucroy Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.
The Purdue Cancer Center, Purdue University, West Lafayette, IN 47907.

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Abstract

Objective—To determine the threshold for acute toxicosis of parenterally administered zinc phthalocyanine tetrasulfonate (ZnPcS4), a candidate second-generation photosensitizer, in mice and evaluate the compound's safety in a phase I clinical trial of ZnPcS4-based photodynamic therapy (PDT) in pet dogs with naturally occurring tumors.

Animals—Male Swiss-Webster mice and client-owned dogs with naturally occurring neoplasms.

Procedures—For the study of acute toxicosis, mice were given graded doses of ZnPcS4. To determine safety, a rapid-titration phase I clinical trial of ZnPcS4-based PDT in tumor-bearing dogs was conducted.

Results—In mice, administration of ≥ 100 mg of ZnPcS4/kg resulted in renal tubular necrosis 24 hours after IP injection. In tumor-bearing dogs, ZnPcS4 doses ≤ 4 mg/kg induced no signs of toxicosis and resulted in partial to complete tumor responses in 10 of 12 dogs 4 weeks after PDT. Tumor remission was observed with ZnPcS4 doses as low as 0.25 mg/kg.

Conclusions and Clinical Relevance—A conservative starting dose of ZnPcS4 was arrived at on the basis of mouse toxicosis findings. Zinc phthalocyanine tetrasulfonate–based PDT was tolerated well by all dogs and warrants further study. The identification of the maximum tolerated dose through traditional phase I clinical trials may be unnecessary for evaluating novel PDT protocols.

Abstract

Objective—To determine the threshold for acute toxicosis of parenterally administered zinc phthalocyanine tetrasulfonate (ZnPcS4), a candidate second-generation photosensitizer, in mice and evaluate the compound's safety in a phase I clinical trial of ZnPcS4-based photodynamic therapy (PDT) in pet dogs with naturally occurring tumors.

Animals—Male Swiss-Webster mice and client-owned dogs with naturally occurring neoplasms.

Procedures—For the study of acute toxicosis, mice were given graded doses of ZnPcS4. To determine safety, a rapid-titration phase I clinical trial of ZnPcS4-based PDT in tumor-bearing dogs was conducted.

Results—In mice, administration of ≥ 100 mg of ZnPcS4/kg resulted in renal tubular necrosis 24 hours after IP injection. In tumor-bearing dogs, ZnPcS4 doses ≤ 4 mg/kg induced no signs of toxicosis and resulted in partial to complete tumor responses in 10 of 12 dogs 4 weeks after PDT. Tumor remission was observed with ZnPcS4 doses as low as 0.25 mg/kg.

Conclusions and Clinical Relevance—A conservative starting dose of ZnPcS4 was arrived at on the basis of mouse toxicosis findings. Zinc phthalocyanine tetrasulfonate–based PDT was tolerated well by all dogs and warrants further study. The identification of the maximum tolerated dose through traditional phase I clinical trials may be unnecessary for evaluating novel PDT protocols.

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