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The hall-mark of modern radiation oncology
Int. _I. Radiation
Oncology
Pergamon
Biol. Phys., Vol. 30, No. 5, pp. 1247-1249, 1994 Copyright 0 I994 ElsevierScienceLtd Printedin the USA. All rights reserved 0360-3016/94 $6.00 + .OO
0360-3016(94)00531-l
??Editorial
THE HALL-MARK OF MODERN RADIATION ONCOLOGY C.NORMANCOLEMANANDMARYANNSTEVENSON Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA “The function of the radiation biologist is to make the clinician think. To lead the way, To point to a new tomorrow. And the lesson in 1993 is, Go molecular young man, (or woman as the case may be). .
To lead the change To improve the patterns of care To help the cancer patient That’s what it’s all about. It may be magic and can’t be done today. But don’t bet that we can’t do it tomorrow!” ASTRO Gold Medal Address, 1993, E. J. Hall (3)
izing radiation related to DNA repair (sublethal and potentially lethal damage) was undertaken, with the postulate that resistant cells may have an excessively potent DNA repair capacity. The microenvironment was important because chronically hypoxic cells were relatively radioresistant. Many of the clinical radiation sensitizers were developed based on these biological concepts (sensitizers of chronically hypoxic cells, DNA repair inhibitors). Figure 2 illustrates some of the newer findings being investigated by radiation biologists. DNA is still considered the critical target of radiation damage and, ultimately, clonogenic cell death. Enzymes that repair x-ray induced DNA damage are being defined, as are enzymes that restore damaged DNA through genetic recombination. Ionizing radiation can activate signal transduction pathways, which in turn can alter the expression of various genes. It is not known for certain how the cell senses xirradiation, particularly at low doses, but there is evidence that DNA damage per se is not required. Thus, the target could be a cellular membrane or cytoplasmic or nuclear protein. When a cell is exposed to X rays, genes are activated and new proteins made. These include growth arrest, cell cycle, and stress response genes. Growth factors and cytokines may be produced and secreted. The cellular microenvironment can alter the radiation response in complex ways. In addition to chronic hypoxia, new factors
In this issue of the Journal (4), the I993 ASTRO Gold Medal winner continues to do what he has done for so many years and for so many radiation oncologists: to pro-
voke us to think. Dr. Hall provides an insightful look into the impact of molecular biology on radiation therapy. Linking clinical observations with the knowledge that is emerging from modern biology, he demonstrates how the many descriptive processes that fill the clinical and classic radiobiological literature may soon be explained by mechanistic studies. To those who trained more than a decade ago, the complexity of the concepts and terminology of modern cellular, molecular, and structural biology are, indeed, daunting. Even more so is the rate of acquisition of new knowledge. However, the fundamental concepts are manageable. Efforts, such as those of Dr. Hall, to provide overviews of the new biology have recently been presented in the radiation oncology literature (1, 5, 7) and excellent textbooks are available that explain the terminology and the bases of the new laboratory techniques (6). How much has radiation biology changed in the last few years? Figure 1 is an illustration of the basic radiobiology taught to trainees about a decade ago. The only molecule of serious emphasis was the DNA. Although effects on cellular membranes were known, DNA was the target of interest. A search for causes of resistance to ion-
Accepted for publication
Reprint requests to: C. Norman Coleman. 1247
22 September 1994.
1248
1. J. Radiation Oncology 0 Biology 0 Physics
Volume 30, Number 5, 1994
Cell membrane
c
In the nucleus: \ 6
-DNA repair enzymes
Fig. 1. “Classic” radiation biology, circa early 1980s (adapted from I). include general nutrient deprivation (&hernia), intermittent, as well as chronic deprivation, and oxidative stress upon reoxygenation. A cell may behave differently by virtue of cell-cell contact or its attachment to the extracellular matrix. Radiation can produce cellular death by activating a suicide process called apoptosis or programmed cell death. The particular genes involved in the evolution of a normal cell to a cancer are being determined. As described by Dr. Hall, these involve abnormal genes, called oncogenes, which produce nonfunctioning or dysfunctioning gene products. Whether a gene is dominant or recessive may be an issue of semantics. An alteration in a single gene may lead to a pathological process being turned continuously “on” as with a ras mutation. ~53 is often considered a recessive mutation as it is necessary to turn “oil” the function of both ~53 alleles. However, there are some ~53 mutations in which a single gene mutation produces an abnormal protein that interacts with the normal ~53
gene product of the other allele, thereby inactivating it. This is referred to as a dominant-negative mutation. Of further interest, the function of normal gene products, such as that of p53 protein, may change based on cellular biochemistry (2). Thus, a normal gene product may function abnormally within a tumor. How important is all of this to the practicing radiation oncologist? The new biology does not reduce the need for continued high quality innovative research in classic radiation biology. There remains a need for in viva studies including fundamental tumor biology, angiogenesis, normal tissue injury, fractionation, and preclinical development of new treatments. We strongly share the opinion of Dr. Hall in that today’s new biology “. . . will revolutionize our concepts of cancer treatment, . . . as surely as night follows day.” There is clearly a lag of years between a scientific discovery and a clinical intervention. The novel intervention may be a prognostic factor (cell proliferation, metastatic potential), a predictive assay (ra-
Cell membrane Apoptosis & other RT-induced processes In the nucleus:
Fig. 2. Radiation
biology-1994
model. To be continuously
updated.
Modem radiation oncology 0 C. N. COLEMAN
diation responsiveness, chemo-resistance), or a new therapy (bioreductive drug, cytokine treatment, gene therapy). The practicing clinical radiation oncologist must be well aware of these upcoming advances to be able to properly represent his/her patient in clinical decision-making, to answer patients’ questions about the latest press release or new research protocol, and to help support the development of improved approaches using radiation therapy. Advances in physical delivery of ionizing radiation (3Dconformal treatment, particles) and other forms of energy (heat, photodynamic therapy) will, at some point, be limited by normal tissue tolerance. Biological approaches will be absolutely necessary to bring the best treatment results to our patients. We are fortunate to be practicing a medical subspeciality which is in the middle of one of the most remark-
AND M. A. STEVENSON
I249
able periods of progress in biology research. Our predecessors in radiation biology and oncology prepared us with the insight to address the questions that, thanks to modem techniques, we are now able to ask and answer. We are grateful to the many radiation biologists who have followed the lead of Eric Hall “to make the clinician think.” SCAROP has recently undertaken an initiative to update the cancer biology curriculum for residency training. To do our best for the cancer patient, we, radiation oncologists, practitioners, academicians, and trainees must enthusiastically embrace Dr. Hall’s admonition” . . . go molecular young man.” The journey is fascinating; the horizons, wide open; and the potential benefits in the diagnosis, prevention, and treatment of cancer are phenomenal. The cost for this journey is far lower than the price to be paid for not taking it.
REFERENCES 1. Coleman, C. N. Beneficial liaisons: Radiobiology meets cel-
lular and molecular biology. Radiother. Oncol. 28: 1-l 5; 1993. 2. Hainut, P.; Milner, J. Redox modulation of ~53 conformation and sequence-specific binding in vitro. Cancer Res. 53:4469-4473; 1993. 3. Hall, E. J. ASTRO Gold Medal: The function of a radiologist is to make the clinician think. Int. J. Radiat. Oncol. Biol. Phys. 20:891-892; 1994. 4. Hall, E. J. Molecular biology in radiation therapy: the potential impact of recombinant technology on clinical practice. Int. J. Radiat. Oncol. Biol. Phys. 30: 10 19-1028; 1994.
5. Maity, A.; McKenna, W. G.; Muschel, R. J. The molecular basis for cell cycle delay following ionizing radiation: A review. Radiother. Oncol. 3 1: 1- 13; 1994. 6. Watson, J. D.; Gilman, M.; Witkowski, J.; Zoller, M. Recombinant DNA. New York: Scientific American Books, W. H. Freeman: 1992. 7. Weichselbaum, R. R.; Hallahan, D. E.; Sukhatme, V.; Dritschilo, A.; Sherman, M. L.; Kufe, D. W. Biological consequences of gene regulation after ionizing radiation exposure. J. Natl. Cancer Inst. 83:480-484; 1991.
Oncology
Pergamon
Biol. Phys., Vol. 30, No. 5, pp. 1247-1249, 1994 Copyright 0 I994 ElsevierScienceLtd Printedin the USA. All rights reserved 0360-3016/94 $6.00 + .OO
0360-3016(94)00531-l
??Editorial
THE HALL-MARK OF MODERN RADIATION ONCOLOGY C.NORMANCOLEMANANDMARYANNSTEVENSON Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA “The function of the radiation biologist is to make the clinician think. To lead the way, To point to a new tomorrow. And the lesson in 1993 is, Go molecular young man, (or woman as the case may be). .
To lead the change To improve the patterns of care To help the cancer patient That’s what it’s all about. It may be magic and can’t be done today. But don’t bet that we can’t do it tomorrow!” ASTRO Gold Medal Address, 1993, E. J. Hall (3)
izing radiation related to DNA repair (sublethal and potentially lethal damage) was undertaken, with the postulate that resistant cells may have an excessively potent DNA repair capacity. The microenvironment was important because chronically hypoxic cells were relatively radioresistant. Many of the clinical radiation sensitizers were developed based on these biological concepts (sensitizers of chronically hypoxic cells, DNA repair inhibitors). Figure 2 illustrates some of the newer findings being investigated by radiation biologists. DNA is still considered the critical target of radiation damage and, ultimately, clonogenic cell death. Enzymes that repair x-ray induced DNA damage are being defined, as are enzymes that restore damaged DNA through genetic recombination. Ionizing radiation can activate signal transduction pathways, which in turn can alter the expression of various genes. It is not known for certain how the cell senses xirradiation, particularly at low doses, but there is evidence that DNA damage per se is not required. Thus, the target could be a cellular membrane or cytoplasmic or nuclear protein. When a cell is exposed to X rays, genes are activated and new proteins made. These include growth arrest, cell cycle, and stress response genes. Growth factors and cytokines may be produced and secreted. The cellular microenvironment can alter the radiation response in complex ways. In addition to chronic hypoxia, new factors
In this issue of the Journal (4), the I993 ASTRO Gold Medal winner continues to do what he has done for so many years and for so many radiation oncologists: to pro-
voke us to think. Dr. Hall provides an insightful look into the impact of molecular biology on radiation therapy. Linking clinical observations with the knowledge that is emerging from modern biology, he demonstrates how the many descriptive processes that fill the clinical and classic radiobiological literature may soon be explained by mechanistic studies. To those who trained more than a decade ago, the complexity of the concepts and terminology of modern cellular, molecular, and structural biology are, indeed, daunting. Even more so is the rate of acquisition of new knowledge. However, the fundamental concepts are manageable. Efforts, such as those of Dr. Hall, to provide overviews of the new biology have recently been presented in the radiation oncology literature (1, 5, 7) and excellent textbooks are available that explain the terminology and the bases of the new laboratory techniques (6). How much has radiation biology changed in the last few years? Figure 1 is an illustration of the basic radiobiology taught to trainees about a decade ago. The only molecule of serious emphasis was the DNA. Although effects on cellular membranes were known, DNA was the target of interest. A search for causes of resistance to ion-
Accepted for publication
Reprint requests to: C. Norman Coleman. 1247
22 September 1994.
1248
1. J. Radiation Oncology 0 Biology 0 Physics
Volume 30, Number 5, 1994
Cell membrane
c
In the nucleus: \ 6
-DNA repair enzymes
Fig. 1. “Classic” radiation biology, circa early 1980s (adapted from I). include general nutrient deprivation (&hernia), intermittent, as well as chronic deprivation, and oxidative stress upon reoxygenation. A cell may behave differently by virtue of cell-cell contact or its attachment to the extracellular matrix. Radiation can produce cellular death by activating a suicide process called apoptosis or programmed cell death. The particular genes involved in the evolution of a normal cell to a cancer are being determined. As described by Dr. Hall, these involve abnormal genes, called oncogenes, which produce nonfunctioning or dysfunctioning gene products. Whether a gene is dominant or recessive may be an issue of semantics. An alteration in a single gene may lead to a pathological process being turned continuously “on” as with a ras mutation. ~53 is often considered a recessive mutation as it is necessary to turn “oil” the function of both ~53 alleles. However, there are some ~53 mutations in which a single gene mutation produces an abnormal protein that interacts with the normal ~53
gene product of the other allele, thereby inactivating it. This is referred to as a dominant-negative mutation. Of further interest, the function of normal gene products, such as that of p53 protein, may change based on cellular biochemistry (2). Thus, a normal gene product may function abnormally within a tumor. How important is all of this to the practicing radiation oncologist? The new biology does not reduce the need for continued high quality innovative research in classic radiation biology. There remains a need for in viva studies including fundamental tumor biology, angiogenesis, normal tissue injury, fractionation, and preclinical development of new treatments. We strongly share the opinion of Dr. Hall in that today’s new biology “. . . will revolutionize our concepts of cancer treatment, . . . as surely as night follows day.” There is clearly a lag of years between a scientific discovery and a clinical intervention. The novel intervention may be a prognostic factor (cell proliferation, metastatic potential), a predictive assay (ra-
Cell membrane Apoptosis & other RT-induced processes In the nucleus:
Fig. 2. Radiation
biology-1994
model. To be continuously
updated.
Modem radiation oncology 0 C. N. COLEMAN
diation responsiveness, chemo-resistance), or a new therapy (bioreductive drug, cytokine treatment, gene therapy). The practicing clinical radiation oncologist must be well aware of these upcoming advances to be able to properly represent his/her patient in clinical decision-making, to answer patients’ questions about the latest press release or new research protocol, and to help support the development of improved approaches using radiation therapy. Advances in physical delivery of ionizing radiation (3Dconformal treatment, particles) and other forms of energy (heat, photodynamic therapy) will, at some point, be limited by normal tissue tolerance. Biological approaches will be absolutely necessary to bring the best treatment results to our patients. We are fortunate to be practicing a medical subspeciality which is in the middle of one of the most remark-
AND M. A. STEVENSON
I249
able periods of progress in biology research. Our predecessors in radiation biology and oncology prepared us with the insight to address the questions that, thanks to modem techniques, we are now able to ask and answer. We are grateful to the many radiation biologists who have followed the lead of Eric Hall “to make the clinician think.” SCAROP has recently undertaken an initiative to update the cancer biology curriculum for residency training. To do our best for the cancer patient, we, radiation oncologists, practitioners, academicians, and trainees must enthusiastically embrace Dr. Hall’s admonition” . . . go molecular young man.” The journey is fascinating; the horizons, wide open; and the potential benefits in the diagnosis, prevention, and treatment of cancer are phenomenal. The cost for this journey is far lower than the price to be paid for not taking it.
REFERENCES 1. Coleman, C. N. Beneficial liaisons: Radiobiology meets cel-
lular and molecular biology. Radiother. Oncol. 28: 1-l 5; 1993. 2. Hainut, P.; Milner, J. Redox modulation of ~53 conformation and sequence-specific binding in vitro. Cancer Res. 53:4469-4473; 1993. 3. Hall, E. J. ASTRO Gold Medal: The function of a radiologist is to make the clinician think. Int. J. Radiat. Oncol. Biol. Phys. 20:891-892; 1994. 4. Hall, E. J. Molecular biology in radiation therapy: the potential impact of recombinant technology on clinical practice. Int. J. Radiat. Oncol. Biol. Phys. 30: 10 19-1028; 1994.
5. Maity, A.; McKenna, W. G.; Muschel, R. J. The molecular basis for cell cycle delay following ionizing radiation: A review. Radiother. Oncol. 3 1: 1- 13; 1994. 6. Watson, J. D.; Gilman, M.; Witkowski, J.; Zoller, M. Recombinant DNA. New York: Scientific American Books, W. H. Freeman: 1992. 7. Weichselbaum, R. R.; Hallahan, D. E.; Sukhatme, V.; Dritschilo, A.; Sherman, M. L.; Kufe, D. W. Biological consequences of gene regulation after ionizing radiation exposure. J. Natl. Cancer Inst. 83:480-484; 1991.