Arthur R. Galbraith

Inhibition of carcinogen-induced pulmonary and mammary carcinogenesis by chalcone administered subsequent to carcinogen exposure.

A study of the capacity of chalcone to inhibit benzo[alpha]pyrene(BP)-induced carcinogenesis of the lungs and forestomach in female A/J mice and N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis in female Sprague-Dawley rats has been carried out. Chalcone, 5 mg/g of diet, had a inhibitory effect on pulmonary adenoma formation (29%) and on mammary tumor formation (49%) when the compound was fed starting one week after final carcinogen administration. Chalcone did not inhibit forestomach tumor formation. In an additional study, chalcone started 4 weeks after MNU and fed for 3-week courses alternating with 3-week courses of control diet for the duration of the protocol also inhibited mammary tumor formation by 49%. The data showing that chalcone has inhibitory effects against both pulmonary and mammary carcinogenesis when given after carcinogen administration provides the basis for further investigations of this and possibly other chalcones as chemopreventive suppressing agents.

N-Acetylcysteine suppression of the proliferative index in the colon of patients with previous adenomatous colonic polyps

This investigation is part of an effort to develop chemoprevention for carcinogenesis of the large bowel. The agent investigated is N-acetylcysteine (NAC). We used as a predictive biomarker, the proliferative index (PI), in a short-term human study. Patients with previous adenomatous colonic polyps are a cohort with increased risk for colon cancer and an increased PI of colonic crypts. They were randomly assigned to an experimental group given 800 mg/day of NAC for 12 weeks or a placebo group. Using proliferative cell nuclear antigen immunostaining, the PI of colonic crypts was measured prior to and after the treatments. The PI of the NAC group was decreased significantly (P < 0.02) while the placebo group showed no difference (P > 0.45). Since this decrease in PI may be an indicator of decreased risk of colon cancer, more extensive studies of the potential of NAC as a chemopreventive agent for colon cancer appear warranted.

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.(Cancer Epidemiol Biomarkers Prev 2007;16(8):1644–50) (Cancer Epidemiol Biomarkers Prev 2007;16(8):1644–50)

Nucleophiles as Anticarcinogens

The objective of the present work was to obtain chemopreventive compounds that can trap direct-acting carcinogens within the lumen of the gastrointestinal tract and thus prevent these carcinogens from attacking tissues of the host. Many direct-acting carcinogens are electrophiles (19, 36). One possible strategy for blocking their action is by trapping them with nucleophiles (electron donors). In the studies to be presented, emphasis has been placed on trapping direct-acting carcinogens in two sites, i.e., the stomach and the large intestine. To some extent different considerations pertain for each.

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.

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.

N-methylnitrosourea–induced carcinoma as a model for laryngeal carcinogenesis.

Preclinical animal models to study laryngeal cancer are nonexistent. The purpose of this study was to describe a novel mice laryngeal cancer model.

Abstract 2129: Effects of talactoferrin on lung adenoma prevention in A/J mice

Talactoferrin is a promising non-toxic solid tumor cancer agent which has met with some success in the treatment of early stage lung cancer clinically in humans. It is well tolerated and early phase clinical trials with this agent demonstrated efficacy and immune stimulation as an oral dendritic cell-mediated immunotherapy agent. We felt the nature of this agent would be suitable in the chemoprevention setting in experimental lung carcinogenesis in a B[A]P mouse model. We utilized 120 seven week old female A/J mice. All groups received Benzo[a]pyrene by oral gavage in three doses of 3mg/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, talactoferrin (Agennix Inc., Indianapolis, IN) at 1.40 and 0.42% of diet, were started one week or eight weeks after last dose of B[a]P. Animals were continued on the feeding schedule, weighed weekly, and monitored for weight loss, attenuation, rough hair coat, or other signs of ill health. 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. The average number of adenomas per animal was 14.04 ± 0.9315 (N=24) in the control group, 18.14 ± 1.448 (N=22) in the early low dose group, 16.70 ± 1.295 (N=23) in the late low dose group, 15.09 ± 1.408 (N=23) in the early high dose group and 14.46 ± 1.213 (N=24) in the late high dose group. We conclude talactoferrin is well tolerated in the A/J mouse model. We also conclude talactoferrin did not inhibit carcinogenesis in A/J mice at a dose range of 420mg/kg/day to 1400mg/kg/day. Citation Format: Donna Seabloom, Arthur Galbraith, Anna Haynes, Jenny Antonides, Alisha Fujita, Beverly R. Wuertz, Vernon Steele, Frank Ondrey, Lee Wattenberg. Effects of talactoferrin on lung adenoma prevention in A/J mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2129. doi:10.1158/1538-7445.AM2014-2129