Biomedical subjects
DE Hallahan
Publications and source records attributed to DE Hallahan.
Radiation-Mediated Gene Expression in the Pathogenesis of the Clinical Radiation Response.
Cells and tissues respond to reactive oxygen intermediates during physiological processes such as inflammation, ischemia, and reperfusion. Ionizing radiation mimics naturally occurring free radicals to produce similar responses. Radiation induces the production of reactive oxygen intermediates and subsequent oxidation of cell membrane, phospholipids, and DNA. This initial event leads to activation of signals (enzymes) within the cells. These activated enzymes produce a cascade of energy transfer within the cell, leading to activation of transcription factors and the transcriptional apparatus. Radiation-inducible genes are then transcribed, leading in part to biological responses to ionizing radiation. Examples of radiation-inducible genes that regulate the biological response include inflammatory mediators and cell cycle regulators. The products of radiation-inducible genes are proteins such as transcription factors, cell adhesion molecules, and cytokines. The importance of identifying the mechanism of radiation-mediated gene expression is that enzyme inhibitors can be used to prevent gene expression. This synopsis of radiation-induced gene expression reviews genes that are induced by x-rays and gamma-rays and categorizes them according to their related biological responses.
Modification of the Radiation Response by the Administration of Exogenous Genes.
Gene therapy combined with radiotherapy represents a new approach for cancer treatment to selectively radio-sensitize malignant cells or protect normal tissues. Examples of gene therapy strategies that modify the biological response to radiation include cytokine-mediated gene therapy and virally directed enzyme/pro-drug therapy (VDEPT). We have proposed the concept of gene therapy targeted by ionizing radiation, whereby a cDNA encoding a cytotoxin or an immunogenic protein that modifies the cellular radiation response is ligated downstream from a radiation inducible promoter. Protein is thus induced in response to irradiation. In this way, radiation acts as a molecular switch to activate transcription of a therapeutic gene. VDEPT incorporates a viral vector system to deliver a gene encoding a pro-drug activating enzyme to malignant cells. After intracellular expression of the enzyme, a nontoxic pro-drug is converted to an active compound to selectively sensitize tumor cells to radiation. We will review current concepts of gene therapy and the studies that show its potential efficacy in the modification of radiation response.