Reduction by Dietary Matrix Metalloproteinase Inhibitor BAY 12-9566N of Neoplastic Development Induced by Diethylnitrosamine, N-nitrosodimethylamine, or 7,12-dimethylbenz(a)anthracene in Rats

• Published in: Drug and chemical toxicology (New York, N.Y. 1978) N.Y. 1978), 2008-01, Vol.31 (3), p.305-316
• Main Authors: Iatropoulos, Michael J., Cerven, Daniel R., deGeorge, George, von Keutz, Eckhard, Williams, Gary M.
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - toxicity; Adenoma - chemically induced; Adenoma - prevention & control; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biphenyl Compounds; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - toxicity; Chemical agents; Chronic bioassay; Diethylnitrosamine - toxicity; Dimethylnitrosamine - toxicity; Drug Screening Assays, Antitumor; Female; Liver Neoplasms - chemically induced; Liver Neoplasms - prevention & control; Lung Neoplasms - chemically induced; Lung Neoplasms - prevention & control; Male; Mammary Neoplasms, Experimental - chemically induced; Mammary Neoplasms, Experimental - prevention & control; Matrix Metalloproteinase Inhibitors; Matrix metallopzoteinase inhibitor; Medical sciences; Neoplasia reduction; Neoplasms - chemically induced; Neoplasms - prevention & control; Organic Chemicals - pharmacology; Phenylbutyrates; Rat; Rats; Rats, Wistar; Sex Factors; Tumors
• ISSN: 0148-0545; 1525-6014
• DOI: 10.1080/01480540701873350

BAY 12-9566N (BAY), which is a substituted 4-biarylbutyric acid and has the properties of a matrix metalloproteinase (MMP) inhibitor, was tested in the accelerated cancer bioassay (ACB). In the ACB, three different genotoxic carcinogens were administered individually to groups of male and female Wistar rats, in initiation (IN) segments lasting 10 weeks, followed by BAY in promotion segments lasting 42 weeks, for a total of 52 weeks of treatment, followed by 12 weeks of recovery. The IN target organs in males were the liver using diethylnitrosamine (DEN), and the lungs, using N-nitrosodimethylamine (NDA), and in females, the mammary gland using 7,12-dimethylbenz(a)anthracene (DMBA). The study consisted of eight groups of 24 rats each as follows: controls (male and female), DEN alone (male), DEN BAY (male), NDA (male), NDA BAY (male), DMBA (female), and DMBA BAY (female). The daily dose of BAY was 240 mg kg in the diet, yielding a cumulative dose of 70,560 mg kg. The cumulative doses of carcinogens were 220 mg kg DEN, 150 mg kg NDA, or 15 mg kg DMBA. No significant difference in body-weight gain pattern was evident between any of the groups at 52 or 64 weeks. Rather, in males, DEN-induced hepatocellular adenomas were reduced with BAY treatment from 29% to 21% (p < 0.05) and carcinomas from 42% to 29% (p < 0.01). Also, in males, NDA-induced pulmonary adenomas were reduced with BAY treatment from 38% to 21% (p < 0.01) and carcinomas from 21% to 4% (p < 0.01). In females, DMBA-induced mammary gland adenomas were reduced from 13% to 4% (p < 0.01) and carcinomas from 54% to 42% (p < 0.05). Thus, BAY produced a consistent and significant reduction of neoplasm development in both genders in three target tissues of carcinogenicity in which neoplasms were induced by three different DNA-reactive initiators. This inhibition may be due to inhibition of MMP, leading to reduced neoplastic growth and development.