Evaluation of a Short-term Rat Mammary Aberrant Focus Assay as a Surrogate Endpoint Biomarker Model to Identify Potential Chemopreventive Agents. The objective of this project is to develop in a short term quantitative in vivo screen involving reduction of aberrant foci produced in the rat or mouse mammary gland by a carcinogen. The responsiveness of a short term rodent model of chemically-induced mammary carcinogenesis to various chemopreventive agents is being evaluated. Included in this characterization is a histological examination that quantitates the presence of intraductal hyperplasia, ductal carcinoma in situ, and adenocarcinoma of the mammary glands. This project is evaluating and comparing the chemopreventive efficacy of ten agents of various mechanistic classes of chemopreventive agents: antimutagens, antiproliferation agents, antioxidants, and antiinflammatory agents under two protocols of exposure. The Maximum Tolerated Dose (MTD) by exposing groups of animals to each agent at five doses is being determined. The agents are being fed either three days prior to carcinogen exposure to 28 days following exposure at which time the animals will be sacrificed (Protocol A below) or feed agents from 27 days following exposure to 56 days following exposure at which time the animals will be sacrificed (Protocol B below). Three week old female Sprague-Dawley rat are being exposed to 50 mg of methylnitrosourea (MNU)/kg body weight. MNU is a carcinogen known to cause mammary carcinomas in mice or rats. The presence of morphologically identifiable SEB (e.g., hyperplasia, atypical hyperplasia, ductal carcinoma in situ, and adenocarcinoma in each animal in each experimental group is being evaluated.
