Rapid Screen for Genotoxicants, Chemoprotectors, and Radioprotectors

Dertinger, Stephen

Abstract

This research project addresses an important problem faced by the chemical and drug industries? their requirement to evaluate the DNA damaging potential of ever larger numbers of new chemical entities in shorter periods of time. This situation presents opportunities for small businesses that are able to provide solutions to these challenges. The work proposed herein addresses industry's need for higher throughput toxicity assessment through the development of an automated in vitro chromosomal damage assay. Chromosome damage will be quantified by flow cytometric micronucleus measurements. Importantly, the methodology that will be developed over the course of this project not only represents a high volume genotoxicant screening system, but also one that can be configured to identify agents which protect against chromosomal damage. This project addresses a stated need of investigators working to develop the next generation of biological response modifiers (BRMs). BRMs that provide chemo- or radio-protection hold great promise in several important arenas, including cancer treatments which are typically dose-limited by normal tissue responses. The identification and development of BRMs have other important applications, and include enhanced protection of our troops during times of war, and also for civilian victims of chemical or radiological terrorist attacks. The planned Phase 1 and Phase 2 efforts have thus been designed to provide a rapid and efficient assay for detecting the genotoxicant, radioprotectant, or chemoprotectant potential of test chemicals. This screening assay will help chemical and drug companies allocate their resources to the most promising candidates, eliminating hazardous entities early in development. Furthermore, by aiding in the identification of next generation BRMs, cancer patients and armed forces will benefit from the availability of chemo- and radio-protectant drugs. ? ? ?