Effects of talactoferrin alpha on lung adenoma prevention in A/J mice June 2, 2016.

Talactoferrin alpha is a promising non-toxic solid tumor cancer agent that met with success in the treatment of early-stage lung cancer clinically in humans. It is well-tolerated, anddendritic cell-stimulation is a target. We tested the efficacy of this agent in a chemoprevention setting in A/J mice. All groups received benzo[a]pyrene (B[a]P) by oral gavage in three doses of 3 mg/kg body weight over the course of one week. Animals were then randomized into 5 groups of 24 mice per group based on weight. Experimental diets oftalactoferrin alpha (Agennix Inc., Indianapolis, IN), at 1.40% and 0.42% of the diet, were started one week or eight weeks after the last dose of B[a]P. Animals were continued on the feeding schedule, weighed weekly, and monitored for toxicity. The study was concluded 16 weeks after administration of B[a]P. The agent was well-tolerated for the duration of the experiment and there was no observable toxicity or weight change. The average number of adenomas per animal was 14.04 ± 0.93 (N=24) in the control group, 18.14 ± 1.45 (N=22) in the early low-dose group, 16.70 ± 1.30 (N=23) in the late low-dose group, 15.09 ± 1.41 (N=23) in the early high-dose group and 14.46 ± 1.21 (N=24) in the late high-dose group. We conclude talactoferrinalpha is well-tolerated. However, it did not inhibit carcinogenesis at a dose of 1.4% or 0.42% of the diet, which equates to human doses of 1.12 g/kg/day or 0.336 g/kg/day.

Fixed-Dose Combinations of Pioglitazone and Metformin for Lung Cancer Prevention.

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.

Safety and Preclinical Efficacy of Aerosol Pioglitazone on Lung Adenoma Prevention in A/J Mice.

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.