Molecular biology: the key to personalised treatment in radiation oncology?

Abstract

ABSTRACT. We know considerably more about what makes cells and tissues resistant or sensitive to radiation than we did 20 years ago. Novel techniques in molecular biology have made a major contribution to our understanding at the level of signalling pathways. Before the ''New Biology'' era, radioresponsiveness was defined in terms of physiological parameters designated as the five Rs. These are: repair, repopulation, reassortment, reoxygenation and radiosensitivity. Of these, only the role of hypoxia proved to be a robust predictive and prognostic marker, but radiotherapy regimens were nonetheless modified in terms of dose per fraction, fraction size and overall time, in ways that persist in clinical practice today. The first molecular techniques were applied to radiobiology about two decades ago and soon revealed the existence of genes/proteins that respond to and influence the cellular outcome of irradiation. The subsequent development of screening techniques using microarray technology has since revealed that a very large number of genes fall into this category. We can now obtain an adequately robust molecular signature, predicting for a radioresponsive phenotype using gene expression and proteomic approaches. In parallel with these developments, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can now detect specific biological molecules such as haemoglobin and glucose, so revealing a 3D map of tumour blood flow and metabolism. The key to personalised radiotherapy will be to extend this capability to the proteins of the molecular signature that determine radiosensitivity. Molecular biology developments have, over the past 20 years, provided us with a remarkable array of techniques, enhancing our understanding of how tumour and normal tissues respond to radiation damage. As these techniques grow increasingly sophisticated, their application should, in theory, present opportunities to improve the effectiveness of radiotherapy.However, as we look at how radiotherapy is performed today we see a discipline founded on 100 years of practice-based, empirical development, recently enhanced by impressive advances in dose delivery and image-guided procedures. These developments have brought us to a point where dose deposition is already highly tailored, to a tolerance of ,2% for most tissues of the body, which is much more accurate than any pharmaceutical agent. Yet, are we really delivering dose where it needs to go for maximal therapeutic gain? Basic radiobiology and the five RsThe interaction of high energy X-ray photons with tissue leads to the ejection of fast electrons from molecules (predominantly water), which in turn go on to generate a wide spectrum of secondary electrons, photons and free radicals. The most reactive of these radicals, OH, is capable of creating further radicals of macromolecules. If these are essential for cellular function, as in the case of DNA, then cell biology will be perturbed and this may lead to cell death.These processes have been known for at leas...

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Cofilin-1 and phosphoglycerate kinase 1 as promising indicators for glioma radiosensibility and prognosis

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