Changes in sub-nuclear structures and functional perturbations: Implications for radiotherapy

The eukaryotic cell nucleus is required to accomplish its functions (e.g., replicating transcription, DNA repair, hmRNA processing, etc.) within the c ontext of a highly organized structure [Wei X, Samarabandu I, Devdhar RS, S iegel Al, Acharya R, Berezney R. 1998. Science 281:1502-1506.], since many cancer-therapeutic modalities utilize the nucleus as target for a cytotoxic outcome. A better understanding of the organizational disruption of sub-nu clear structures and subsequent loss of nuclear function is the key to know ing both the mechanism of action of, and the basis of cellular sensitivity to, therapeutic agents such as ionizing radiation. With this prospect, we e xamine four examples in which changes in specific nuclear structures or fun ctions lead to significant therapeutic end points, e.g. cell death, radiose nsitization, or the intrinsic radioresistance of tumor cells. The inter-rel ationships delineated in these examples provide a paradigm that delineates a relationship between disruption of nuclear organization, loss of function and a point of intervention that affects a therapeutic outcome. The exampl es specifically address issues related to radiation and thermal therapy. Ho wever, the concepts that result from these studies are translatable to othe r cancer therapeutic modalities. In addition, the results echo a basic prin ciple that proper nuclear organization is critical to the maintenance of ce llular viability and genomic stability. (C) 2001 Wiley-Liss, Inc.