Development of Chemopreventive Strategies for Radiation-Induced Cancer: Targeting Radiation-Induced Genetic Alterations

Abstract

Carcinogenesis is a multistage process involving dysregulation of signal transduction and cell cycle pathways. This dysregulation results in specific molecular and genetic alterations, including gene amplification, mutations, and chromosomal rearrangements. These aberrations can be measured to provide a novel means to assess carcinogenic risk or as targets for chemointervention. Recent human and in vivo studies have demonstrated that genetic alterations, such as oncogenes and oncoproteins, were observed in preneoplastic tissues or serum following exposure to chemical carcinogens or low-level radiation (LLR). Identification of preneoplastic changes following radiation exposure may provide information that will allow development of LLR chemopreventive strategies. Radiation carcinogenesis studies in vivo with a lung tumor model showed that a low-dose cobalt-60 radiation exposure induced persistent time-dependent genetic alterations, such as elevated ras expression. This radiation exposure also resulted in lung tumor formation in 26% of the irradiated animals at 232 days after irradiation. A significant and progressive increase in ras oncogene expression was measured using Northern blot analysis in 80% of the irradiated animals over the duration of the experiment. Pharmacological intervention strategies are being tested using buthionine-[S,R]-sulfoximine (BSO). BSO has been previously shown to down-regulate ras expression. Administration of BSO prevented radiation-induced changes in ras mRNA levels in this lung tumor model. Further studies are being conducted with an LLR-induced leukemia model in which detection of circulating levels of oncoproteins will be more feasible. Based on these preliminary results and on its clinical efficacy and low clinical toxicity, BSO warrants further study as an LLR chemopreventive agent. Furthermore, this strategy to target LLR-induced preneoplastic alterations may be an effective means of developing modulators of LLR-induced cancers.