Chemoprevention of Lung Carcinogenesis by Dietary Nicotinamide and Inhaled Budesonide.

Nicotinamide, the amide form of vitamin B3, and budesonide, a synthetic glucocorticoid used in the treatment of asthma, were evaluated to determine their individual and combinational chemopreventive efficacy on benzo(a)pyrene-induced lung tumors in female A/J mice. Nicotinamide fed at a dietary concentration of 0.75% significantly inhibited tumor multiplicity. Nicotinamide by aerosol inhalation at doses up to 15 mg/kg/day did not result in a statistically significant reduction in tumor multiplicity. Finally, dietary nicotinamide was administered with aerosol budesonide and tumor multiplicity reduced by 90% at 1 week and 49% at 8 weeks post last carcinogen dose. We conclude nicotinamide is an effective and safe agent for lung cancer dietary prevention at both early- and late-stage carcinogenesis and that efficacy is increased with aerosol budesonide. Combination chemoprevention with these agents is a well-tolerated and effective strategy which could be clinically advanced to human studies.

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.

N-methylnitrosourea­induced carcinoma as a model for laryngeal carcinogenesis.

BACKGROUND: Preclinical animal models to study laryngeal cancer are nonexistent. The purpose of this study was to describe a novel mice laryngeal cancer model. METHODS: A total of 18 six-week-old A/J mice were used. Animals underwent microdirect laryngoscopy, superficial larynx scratching, and instillation of N-methyl-N-nitrosourea (MNU) at 2 different concentrations (15 µL and 30 µL) or dimethyl sulfoxide (DMSO) to the control group directly to the larynx. Mice received a total of 5 instillations of MNU or DMSO at 1-week intervals. Mice were euthanized at 20 and 30 weeks after the last intervention and laryngeal histology was analyzed. RESULTS: Laryngeal instillation of MNU caused a 60% cancer conversion in the study group. CONCLUSION: Our findings demonstrate the feasibility of developing a murine laryngeal carcinogenesis model using direct topical instillation of MNU. This is the first murine model of laryngeal cancer and has great potential for evaluating new agents for chemoprevention and treatment for laryngeal carcinoma.

A method of producing carcinoma in upper aerodigestive tree and esophagus of the Syrian golden hamster using wounding and instillation of N-methylnitrosourea.

Details of a method for producing carcinoma of the aerodigestive tree of the Syrian golden hamster and the use of this model to evaluate putative agents for chemoprevention of these carcinomas are described. The method produces a majority of squamous carcinomas of the trachea and glottis that follow squamous metaplasia of respiratory epithelium. In addition, seen are adenocarcinomas arising in glands of the respiratory tree. Squamous carcinomas of the digestive epithelium arise in primary squamous epithelium. These tumors of digestive epithelium have a growth pattern that differs from that of the respiratory epithelium in that they grow and invade without filling the epithelial layer with tumor cells.