Discovery and Canine Preclinical Assessment of a Nontoxic Procaspase-3–Activating Compound

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 18; pp. 7232 - 7241
• Main Authors: Peterson, Quinn P., Hsu, Danny C., Novotny, Chris J., West, Diana C., Kim, Dewey, Schmit, Joanna M., Dirikolu, Levent, Hergenrother, Paul J., Fan, Timothy M.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2010
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Caspase 3 - metabolism; Dog Diseases - drug therapy; Dog Diseases - enzymology; Dog Diseases - pathology; Dogs; Enzyme Activation - drug effects; HeLa Cells; Humans; Hydrazones - pharmacokinetics; Hydrazones - pharmacology; Hydrazones - toxicity; Jurkat Cells; Lymphoma, B-Cell - drug therapy; Lymphoma, B-Cell - enzymology; Lymphoma, B-Cell - pathology; Lymphoma, B-Cell - veterinary; Male; Medical sciences; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - toxicity; Tumors; U937 Cells; Fissipedia; Evaluation; Carnivora; Vertebrata; Mammalia; Animal; Preclinical trial; Dog
• DOI: 10.1158/0008-5472.CAN-10-0766
• ISSN: 0008-5472; 1538-7445

A critical event in the apoptotic cascade is the proteolytic activation of procaspases to active caspases. The caspase autoactivating compound PAC-1 induces cancer cell apoptosis and exhibits antitumor activity in murine xenograft models when administered orally as a lipid-based formulation or implanted s.c. as a cholesterol pellet. However, high doses of PAC-1 were found to induce neurotoxicity, prompting us to design and assess a novel PAC-1 derivative called S-PAC-1. Similar to PAC-1, S-PAC-1 activated procaspase-3 and induced cancer cell apoptosis. However, S-PAC-1 did not induce neurotoxicity in mice or dogs. Continuous i.v. infusion of S-PAC-1 in dogs led to a steady-state plasma concentration of ∼10 μmol/L for 24 to 72 hours. In a small efficacy trial of S-PAC-1, evaluation of six pet dogs with lymphoma revealed that S-PAC-1 was well tolerated and that the treatments induced partial tumor regression or stable disease in four of six subjects. Our results support this canine setting for further evaluation of small-molecule procaspase-3 activators, including S-PAC-1, a compound that is an excellent candidate for further clinical evaluation as a novel cancer chemotherapeutic. Cancer Res; 70(18); 7232–41. ©2010 AACR.