Kevin Harrington, The Institute of Cancer Research, London, UK
The 4 Rs of radiobiology were initially described to provide a means of understanding the success or failure of localised radiotherapy. Differential repair of tumour and normal cells between treatment fractions, redistribution of cells into more or less radiosensitive phases of the cell cycle, repopulation of tumour cells between fractions and reoxygenation of tumour cells during treatment were all invoked to explain the overall outcome of a course of radiotherapy. Later, intrinsic radiosensitivity was added as the 5th R of radiobiology. At the time, this represented an admission of our inability to explain, at the mechanistic level, the different radiocurabilities of diseases like seminoma, lymphoma, glioma and melanoma.
Nonetheless, the 5 Rs have been extremely important as a framework within which to examine new therapeutic strategies from the point of view of both tumour and normal cells. Each of the Rs can be viewed as a twin-edged sword, such that changes can occur in either direction to increase or decrease the net therapeutic effect. For example, tumour cells with defects in their DNA repair pathway are more likely than adjacent normal cells to die following a dose of radiation. However, the aberrant DNA repair pathway may already have allowed the tumour cell to accumulate non-lethal mutations in other important genes that allow it to tolerate unrepaired DNA damage (or to repair it in an inaccurate fashion that enhances genetic instability). In similar fashion, the enhanced tumour cell division that occurs during a course of radiotherapy is usually seen as the driving force behind accelerated repopulation, but it may also make a tumour cell more susceptible to radiation-induced death by driving it into mitosis with potentially lethal unrepaired DNA damage.
Insights into the molecular biology of cancer now allow us to reinterpret the classical 5 Rs of radiobiology in terms of their underlying mechanisms. The particular strength of this approach is that it leads naturally into a discussion of potential new targeted therapies that may favourably modulate the tumour response and increase the therapeutic index. Specific examples of how knowledge of the molecular biological basis of the radiation response has shaped our current approach to cancer treatment will be discussed. In addition, future directions will be explored.