The explosion of new knowledge about radiation sensitivity and radiation biology is such that even the scholarly, relatively extensive review of the subject authored by Drs. Rosen, Fan, Goldberg, and Rockwell covers but a small proportion of this vast, complex topic.
In both parts 1 and 2 of their article, Rosen et al emphasize the large number of exciting new technical advances in the delivery of radiation therapy that will increase radiation dose delivery to the tumor and decrease the dose to normal tissue. According to the authors, the ability to deliver conformal radiation therapy will (1) allow for tighter field marginswith some risk of underdosing the tumor at those margins; (2) permit the delivery of a heterogeneous dose within the target (ie, a boost within the field that may allow for shorter treatment time and more dose-intensive radiation therapy); and (3) require even more precise tumor imaging to avoid marginal misses.
Any dose increment achieved by the use of photons, brachytherapy, particles, and/or systemically administered radiation therapy will eventually be limited by normal tissue tolerance, however. Advances in the use of radiation (and other forms of energy) will require biological therapies along with the best technical treatmentsa point emphasized by Rosen and colleagues.
How, then, does a technically based field, such as radiation therapy, best utilize the many biological advances outlined by Rosen et al? Radiation oncology is one of the few specialties that rests on four pillars: medicine, physics, biology, and chemistry. Are these truly independent disciplines, however, or just different facets of a complex biological process?
Radiation therapy is often conceptualized as isodose curves, with isodoses viewed as being akin to isobars or isotherms on a weather map or contour lines on a geological map. However, radiation dose is much more complex than what one sees on color-washed contour figures. When a dose of 1 Gy of x-rays (low linear-energy transfer radiation) is delivered to a cella dose that is half the typical clinical fraction (1.8 to 2 Gy)approximately 70% of the cells will survive. Yet, there are millions of lesions created in the nucleus and likely millions created in the cytoplasm, the vast majority of which are not permanent. Nevetheless, as illustrated by the figures in the paper by Rosen et al, the cell does respond.
Furthermore, unlike drugs, radiation therapy is not limited by pharmacokinetics, and when one looks at the subcellular distribution of ionizations (track structure) at the nanometer range, one sees areas of more and less intense ionization, that is, there is dose heterogeneity.
When one thinks about radiation dose, a concept that I consider to be useful is focused biology. When one recognizes the many biological perturbations that result from radiation therapy (as outlined by Rosen et al), one can envision two interrelated paths for modifying the radiation response. The primary focus is on enhancing DNA damage, because unrepaired DNA double-strand breaks are important steps in cell death. A second approach, conceptualized by Coleman et al, centers on perturbing cellular homeostasis, perhaps by altering a signal transduction pathway, tendency toward apoptosis, or redox state, such that the cell, when subsequently irradiated, will respond differently.
For the tumor cell, one would strive to enhance cell death, and for the normal tissue, to reduce the probability of death (assuming that this did not lead to the persistence of cells with deleterious mutations). Pathways available for modifying radiation (altering radiation sensitivity) are numerous. Figure 1 illustrates some of the many potential targets for intervention. As illustrated, the tumor is far more complex than a cancer cell in tissue culture.
Elucidating the Precise Mechanisms of Response to Radiation
Probably one of the more daunting challenges is elucidating exactly how cells and tissues sense and respond to radiation. As summarized by Rosen et al, cellular and normal tissue response to radiation varies greatly. Although there is a tendency to use linear diagrams to illustrate cellular response processes, the cell is anything but linear, owing to the cross-talk among pathways (eg, the signal transduction pathways), stimulatory and inhibitory pathways (eg, proapoptotic and antiapoptotic molecules), and numerous cycles (eg, the cell cycle and protein synthesis and degradation). The cell behaves more like a neural network than a linear process; consequently, one perturbation may produce a very surprising effect elsewhere in the cell and organism.
Newer technology is providing the means for attaining a better understanding of this myriad of interrelated processes: The complementary DNA (cDNA) expression microarrays allow for the interrogation of many thousands of genes within the cell. However, gene expression is only part of the story, as protein-protein interactions control various processes, including post-translational protein modification and degradation.
With respect to the development of new treatments, a better awareness of the targets shared by a range of tumors and others shared by normal tissues will likely yield a rational and judicious number of therapies. New approaches to drug development, such as combinatorial chemistry, will produce a myriad of chemical structures that can be used to modulate a biological process. Our job as translational scientists is to bring the drugs and targets together in the right place at the right time in the right concentrations.
Ultimately, many of the solutions will result from our ability to use an enormous amount of informationone outgrowth of the emerging field of bio-informatics. But how will all of this new information be interfaced with radiation biology and radiation sensitivity?
Many of the newer therapies, such as antiangiogenic agents, will likely be cytostatic, requiring that the cell be killed by one of the conventional approaches of radiation therapy and/or chemotherapy. Molecular and functional imaging of biological response will allow for better definitions of tumor vs normal tissue and may permit the assessment of tumor response very early in the treatment course, thereby enabling us to determine whether the therapy is, indeed, effective. If, as has been suggested, late radiation-induced tissue injury is a chronic, ongoing process, it may be possible to use higher treatment doses, with subsequent measures to reverse tissue damage. Ultimately, when the various genetic polymorphisms are understood, we may be able to tailor the doses of agents to the normal tissue, as well as to the tumor mutation pattern in each individual patient.
The information presented by Rosen and colleagues helps demarcate a new paradigm in radiation oncology, ie, focused biology. According to this new paradigm, radiation therapy not only will directly affect tumor cell killing by inducing DNA damage but also will alter the cellular homeostatic mechanisms. This alteration of homeostasis will enable a potentially toxic drug to be administered in a low enough dose so that only those cells within the radiation beam (delivered either locally or systemically with radiolabeled antibodies or ligands) will be permanently damaged.
With the posthuman genome era almost upon us, reviews such as the one written by Rosen et al will continue to provide the oncology community with a fresh perspective on radiation oncology and the many ways in which the oncologic disciplines can work toward improved cancer treatment and prevention. Facilitating the translation of novel molecular radiation oncology approaches to the clinic is one of the goals of the new Radiation Oncology Sciences Program at the National Cancer Institute.