Chemoprevention of radiation-induced cancer in vitro and in vivo: therapies that target radiation-induced molecular markers

A.C. Miller, PhD

Armed Forces Radiobiology Research Institute, Bethesda, MD USA

AIM: Since previous studies demonstrated that a combination of radiation-induced molecular changes may be useful early diagnostic molecular biomarkers for radiation carcinogenesis we tested two nontoxic pharmacological agents that target radiation-induced oncogenesis to prevent the development of radiation-induced cancer. METHODS: An in vitro transformation assay and a rodent leukemogenesis bioassay were used to examine radiation-induced oncogene activation, transformation, and carcinogenesis. The differentiation inducer, phenylacetate (PA) and the steroid, androstenediol (AED) were tested for their ability to prevent neoplastic growth in vitro and in vivo. RESULTS: Both PA and AED suppressed radiation-induced neoplastic transformation in vitro concomitant with an inhibition of specific molecular alterations. Animal studies demonstrated that radiation exposure could induce preneoplastic oncogenic alterations, i.e., increased ras, expression, at long times post-radiation. Animals pretreated with PA or AED showed a significant reduction in the number of radiation-induced leukemias in contrast to untreated, irradiated animals. CONCLUSIONS: These findings suggest that PA and AED can prevent radiation-induced neoplastic growth associated with a suppression of radiation-induced changes in the ras oncogene.

KEY WORDS: chemoprevention, radiation, oncogenesis, leukemogenesis, biomarker, ras.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Prevention.