title: Safety and Preclinical Efficacy of Aerosol Pioglitazone on Lung Adenoma Prevention in A/J Mice.
abstract: Pioglitazone is a PPARγ agonist commonly prescribed for the clinical treatment of diabetes. We sought to expand its use to lung cancer prevention in a benzo[a]pyrene (B[a]P) mouse model with direct lung delivery via inhalation. Initially, we conducted inhalational toxicity experiments with 0, 15, 50, 150, and 450 μg/kg body weight/day pioglitazone in 40 A/J mice. We examined the animals for any physical toxicity and bronchoalveolar lavage fluids for inflammatory and cytotoxicity markers. Doses up to and including 450 μg/kg bw/d failed to demonstrate toxicity with aerosol pioglitazone. For chemoprevention experiments, A/J mice were randomized to treatment groups of inhaled doses of 0, 50, 150, or 450 μg/kg bw/d pioglitazone 1 or 8 weeks after the last dose of B[a]P. For the early treatment group, we found up to 32% decrease in lung adenoma formation with 450 μg/kg bw/d pioglitazone. We repeated the treatments in a second late-stage experiment and found up to 44% decreases in lung adenoma formation in doses of pioglitazone of 150 and 450 μg/kg bw/day. Both the early- and the late-stage experiments demonstrated biologically relevant and statistically significant decreases in adenoma formation. We conclude that aerosol pioglitazone is well-tolerated in the A/J mouse model and a promising chemoprevention agent for the lower respiratory tract. Cancer Prev Res; 10(2); 124-32. ©2016 AACR.
authors.affiliation: AeroCore Inhalation Testing, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Donna E
authors.initials: DE
authors.lastname: Seabloom
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Galbraith
authors.affiliation: AeroCore Inhalation Testing, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Haynes
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Antonides
authors.affiliation: AeroCore Inhalation Testing, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.|Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Beverly R
authors.initials: BR
authors.lastname: Wuertz
authors.affiliation: Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Miller
authors.affiliation: Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Miller
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland.
authors.forename: Chen S
authors.initials: CS
authors.lastname: Suen
authors.affiliation: Comparative Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: AeroCore Inhalation Testing, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota. ondre002@umn.edu.|Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Ondrey
mesh_terms: D000236:Adenoma / Q000473:pathology*; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018890:Chemoprevention / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D000077205:Pioglitazone; D011897:Random Allocation; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000336:Aerosols; D000970:Antineoplastic Agents; D045162:Thiazolidinediones; D000077205:Pioglitazone