Biological Basis of Radiation Sensitivity
Biological Basis of Radiation Sensitivity
Rosen and colleagues have provided a comprehensive review of the biological basis of radiation sensitivity, including recent insights into the DNA damage response. They correctly emphasize that local control of tumors is still a major clinical problem, and that a better understanding of the biological basis for radiation resistance/sensitivity has significant potential to be exploited for therapeutic gain. They also assert that further progress in local tumor control is unlikely to be achieved by technologic improvements in the delivery of such radiation therapies as three-D (3D) conformal radiotherapy, intensity-modulated radiation therapy (IMRT), altered fractionation, or even chemosensitization.
Has Radiation Delivery Truly Been Optimized?
The assertion that technologic improvements in radiation delivery are unlikely to lead to further progress would probably be debated by many in the radiation oncology field, who devote their entire careers to optimizing dose delivery. However, it is true that optimization of dose delivery will eventually reach a maximum, beyond which further improvements cannot be achieved. The issue is whether or not we are now at or near that level.
To say that fractionation schedules have been fully explored and optimized seems to be somewhat premature. Because accelerated fractionation or hyperfractionation has had less of an impact on locoregional tumor control than was anticipated in, for example, the European Organization for Research and Treatment of Cancer (EORTC) head and neck cancer trials, enthusiasm for this approach has waned. However, it is certainly possible that the selection of patients for accelerated fractionation and hyperfractionation has not yet been optimized.
The suggestion that chemosensitization approaches have also been maximized seems too inclusive: It may be true that there is little room for maneuvering with respect to the use of existing drugs in chemoradiation regimens. But how will knowledge of the biological mechanisms of chemosensitization be exploited, without some form of a designer drug that may or may not show independent cytotoxicity? Attempts to exploit our knowledge of molecular mechanisms in the form of gene therapy have thus far been hampered by problems related to delivery of the genetic vector. Molecular mechanisms may best be manipulated by small moleculesan approach now being actively pursued by many investigators.
Notwithstanding the controversial statements made in the introduction of this two-part review, the paper is clearly organized, and the writing should, for the most part, be easily understood by the general audience. The article could serve as a useful introduction to radiation biology teaching courses aimed at residents and fellows, as well as provide a timely update for established staff. Indeed, the remarkable speed of progress in the field of radiation biology has resulted in a situation in which reviews written only a few years ago are already out of date.
I will take issue with a few topics, not as a criticism of the article by Rosen et al, but more to convey what an exciting field molecular radiation biology has become. Part 1 of the article, which focuses on radiation tolerance, provides a logical sequence of possible events that may contribute to response to radiation. The seven clinical determinants of late-tissue damage are listed; however, in the spirit of a more modern approach, the seventh determinant (individual genetic factors that may affect the intrinsic cellular radiosensitivity) could perhaps, even at this stage, be categorized further. Although this is the subject of part 2 of the article, to crowd genetic factors beneath one umbrella is to overcondense this expanding field. The authors appear to be falling victim to the very traditional thinking that they are trying to change.
Does Genetic Instability Always Correlate With Radiation Sensitivity?
One area of interest that has not yet been explored fully is whether radiation sensitivity always correlates with radiation mutability or carcinogenesis. The extent of radiation sensitivity of ataxia-telangiectasia (A-T) heterozygotes is modest, but the magnitude of cancer predisposition may be greater. Cancer predisposition in A-T heterozygotes has been the subject of much analysis during the last few years, particularly in relationship to breast cancer. Although recent evidence has undermined this relationship, these data did not take into account the possibility of a radiation-induced predisposition.
Other genotypes may predispose to genetic instability without predisposing to radiation sensitivity; p53 deficiency may fall into this category. Depending on other coexisting genetic changes, inactivation of the p53 gene can predispose to both radiation resistance and radiation sensitivity. However, in many cell types, such as murine embryo fibroblasts, inactivation of this gene does not predisposes to any significant change in radiation-induced cell killing. However, loss of p53 function always predisposes to genetic instability, as judged by many different end points.
Carriers of mutations in breast cancer susceptibility genes, BRCA1 or BRCA2, may have a similar phenotype as A-T heterozygotes. Recent evidence suggests that ataxia-telangiectasia, mutated (ATM), p53, and BRCA1/2 genes are linked in a DNA damage-signaling pathway that also involves the human homologs of the yeast checkpoint genes, CHK1 and CHK2.
Does Radiation Sensitivity Stem From Cell-Cycle Checkpoint or DNA Repair Defects?
An interesting dilemma that has faced radiation biologists for years is whether radiation sensitivity arises from a defective cell-cycle checkpoint, or whether it is due to an intrinsic defect in DNA repair. This apparently simple distinction has become more complex of late, because of the discovery of proteins that clearly function in both pathways. The sensing of DNA damage is probably the common factor, and repair and cell-cycle checkpoints may feature separate downstream pathways; the ATM protein, along with the related Nijmegen breakage syndrome (NBS1) protein, likely functions as a DNA damage sensor.
The relationship among DNA damagesensing pathways, the activation of apoptosis, and the development of radiation sensitivity is of critical importance. Rosen et al emphasize the significance of the association between p53 and Bax, particularly their inactivation in tumor cells. Whereas the importance of p53 inactivation in human tumors is certain, it seems less likely that this occurs only to stop Bax activation. Bax knockout mice or cells retain the ability to undergo p53-dependent apoptosis, implying that not all p53-mediated apoptosis is Bax dependent.
Indeed, an interesting question is, exactly how important is apoptosis as a determinant of radiation-induced cell killing in tumor cells? Frequently, tumor development is associated with the inactivation of apoptosis. Furthermore, bcl-2 can be overexpressed in tumor cells to inhibit apoptosis, but this does not always induce radiation resistance.
This statement should not be interpreted to mean that apoptosis plays no role in tumor-cell deathreactivation of apoptosis may, indeed, be a very important means of enhancing cell death. Rather, the statement emphasizes that cell death can be achieved via multiple pathways. Rosen et al describe the diversity of pathways that can regulate or influence apoptosis; the list is enlarging each year.
The key to understanding radiation sensitivity lies in a comprehension of the relationships within the critical DNA damagesensing pathways: DNA damage will produce different outcomes depending on the cell type and growth conditions, as well as the phase of the cell cycle.
This review is a good wake-up call to the brave new world of radiation oncologya world in which molecular biology and cancer genetics have assumed prominent roles. Radiation oncologists need to embrace this new world in their thoughts and strategies. If we do not, the specialty will be left behind merely to tinker with technology.
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