Overview
Radiation-Induced Cytogenetic Damage as a Predictor of Cancer Risk for Protons and Fe Ions
Principal Investigator:
Jerry R. Williams, Sc.D.
Organization:
Johns Hopkins University School of Medicine
Technical Summary
This project has made several key findings that describe, in detail, chromosomal damage induced by three model space radiations: photons, energetic protons and energetic iron-ions (Fe-ions). The large number of data produced provide new insights into the relative potency of these radiations to induce different types of aberrations in multiple cell types: human lymphocytes, human mammary cells, rat mammary cells (in vivo and in vitro) and multiple forms of human colorectal tumor cells that have specific modulations of cancer-relevant genes. Further, we have investigated the induction of these radiations when used in fractionated or protracted time patterns in human lymphocytes, these data providing a paradigm for extrapolation of data from acute exposure to other exposure patterns. Further, the analysis of multiple aberrations per cell may be a "signature" for the dose and quality of radiation that induced these damages. We observe specific changes in induction of chromosome aberrations in cells that are deficient in expression of p53, p21 and 14-3-3-sigma, demonstrating that early changes in cells may render them more susceptible to further genetic damage induced by the three model space radiations. These data also provide new insights into the mechanisms of molecular biology by which cells process radiation damage. We have also measured clustering of multiple aberrations in individual cells so that Poisson analysis can be used to consider the relative influence of radiation quality on multiple events. Finally, we have suggested a new model for the dose response of cells to these radiations, focusing on induced cellular processing of radiation damage. Our model, that we term the subalpha- alpha- omega (SAO) model, provides a new structure for mathematical paradigms for testing whether chromosome aberrations can be used as a surrogate marker in estimating cancer risk. Our data on chromosome aberrations, when combined with the outcome of parallel studies in carcinogenesis in the Sprague-Dawley Rat, will provide a direct comparison between the rate of induction of chromosome aberrations in mammary epithelial cells with the rate of induction of mammary cancer in the same animal model over the same dose-ranges.
This project's funding ended in 2000