In vitro Cytotoxicity and Pharmacokinetic Evaluation of Pharmacological Ascorbate in Dogs

Frontiers in Veterinary Science

Yeon-Jung Seo¹  Benjamin K. Schneider¹  Jonathan P. Mochel¹  Garry R. Buettner²  Melissa A. Fath²  Brett A. Wagner²  Chad M. Johannes³  Margaret L. Musser³  Alyssa L. Mahaffey³ 

[1] Biomedical Sciences, Iowa State University, Ames, IA, United States;Free Radical and Radiation Biology Program, The University of Iowa, Iowa City, IA, United States;Veterinary Clinical Sciences, Iowa State University, Ames, IA, United States;

关键词: canine;    vitamin C;    high-dose;    osteosarcoma;    intravenous;   

DOI  :  10.3389/fvets.2019.00385

来源: DOAJ

【 摘 要 】

Background: High-dose, pharmacological ascorbate (P-AscH−) is preferentially cytotoxic to human cancer cells in vitro. Investigations on the efficacy of P-AscH− as an adjuvant treatment for multiple human cancers are on-going, but has yet to be formally investigated in dogs. The primary objectives of this study were to determine the pharmacokinetic (PK) profile of P-AscH− in healthy Beagle dogs and the effects of P-AscH− on canine osteosarcoma cells in vitro.Methods: Eight purpose-bred, healthy, spayed female Beagle dogs, between 20 and 21 months old, and 8–10 kg were administered two doses of P-AscH− (550 or 2,200 mg/kg) via intravenous infusion over 6 h, on separate days. Plasma ascorbate concentrations were measured at 12 time points during and after infusion for PK analysis using nonlinear mixed-effects (NLME) and non-compartmental analysis (NCA). Clonogenic assays were performed on 2 canine osteosarcoma cell lines (D-17 and OSCA-8) and canine primary dermal fibroblasts after exposure to high concentrations of ascorbate (75 pmoles/cell).Results: Plasma ascorbate levels in the dogs peaked at approximately 10 mM following 2,200 mg/kg and returned to baseline 6–8 h after dosing. Minor adverse effects were seen in two dogs. Ascorbate (75 pmoles/cell) significantly decreased survival in both the osteosarcoma cell lines (D-17 63% SD 0.010, P = 0.005; OSCA-8 50% SD 0.086, P = 0.026), compared to normal fibroblasts (27% SD 0.056).Conclusions: Pharmacological ascorbate is preferentially cytotoxic to canine-derived cancer cells. High levels of ascorbate can be safely administered to dogs. Further studies are needed to determine the effects of P-AscH− on canine patients.

【 授权许可】

Unknown