title: Fixed-Dose Combinations of Pioglitazone and Metformin for Lung Cancer Prevention.
abstract: Combination treatment with pioglitazone and metformin is utilized clinically in the treatment of type II diabetes. Treatment with this drug combination reduced the development of aerodigestive cancers in this patient population. Our goal is to expand this treatment into clinical lung cancer chemoprevention. We hypothesized that dietary delivery of metformin/pioglitazone would prevent lung adenoma formation in A/J mice in a benzo[a]pyrene (B[a]P)-induced carcinogenesis model while modulating chemoprevention and anti-inflammatory biomarkers in residual adenomas. We found that metformin (500 and 850 mg/kg/d) and pioglitazone (15 mg/kg/d) produced statistically significant decreases in lung adenoma formation both as single-agent treatments and in combination, compared with untreated controls, after 15 weeks. Treatment with metformin alone and in combination with pioglitazone resulted in statistically significant decreases in lung adenoma formation at both early- and late-stage interventions. Pioglitazone alone resulted in significant decreases in adenoma formation only at early treatment intervention. We conclude that oral metformin is a viable chemopreventive treatment at doses ranging from 500 to 1,000 mg/kg/d. Pioglitazone at 15 mg/kg/d is a viable chemopreventive agent at early-stage interventions. Combination metformin and pioglitazone performed equal to metformin alone and better than pioglitazone at 15 mg/kg/d. Because the drugs are already FDA-approved, rapid movement to human clinical studies is possible. Cancer Prev Res; 10(2); 116-23. ©2017 AACR.
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|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: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|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: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|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: Mark Steven
authors.initials: MS
authors.lastname: Miller
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
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: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. ondre002@umn.edu.|AeroCore Inhalation Testing, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota.|Department of Otolaryngology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Ondrey
mesh_terms: D000236:Adenoma / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018890:Chemoprevention / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000473:pathology* / Q000517:prevention & control; D008687:Metformin / Q000008:administration & dosage; D051379:Mice; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage
chemical_list: D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D008687:Metformin; D000077205:Pioglitazone