Biologic Basis for Radiation Oncology
Biologic Basis for Radiation Oncology
Drs. Coleman and Stevenson have done a superb job in covering diverse aspects of biology relevant to clinical radiotherapy. They note that recent advances in understanding DNA repair may lead to practical applications in radiotherapy. For example, a dual benefit of unraveling DNA repair mechanisms may be to identify which tumors are the most likely to respond to therapeutic radiation and which patients are most likely to develop radiation-induced tumors. The authors point out that gene induction observed in vitro following large radiation doses may not necessarily be relevant to doses employed clinically. Coleman and Stevenson highlight the importance of defining the sequence of genes induced by radiation in clinically relevant doses.
Since the submission of this article, Hallahan et al have reported that gene therapy can be spatially and temporally controlled by ionizing radiation by employing radiation-inducible promoters linked to toxins . In a broader context, gene therapy also is likely to be combined with radiotherapy employing constitutive promoters. One example is the use of the cytosine deaminase gene in combination with the prodrug flucytosine (Ancobon) to achieve radiosensitization by conversion of flucytosine to fluorouracil .
Cell-cycle progression is likely to be another target for modifying the therapeutic ratio. It is of historical interest that the first genetically defined checkpoint, the G2 block in Saccharomyces cerevisiae, was described using radiation as the prototypical DNA-damaging agent.
Intriguing Questions About Aptosis
The authors discuss apoptosis and p53 in a concise fashion and raise an intriguing question about the relative contributions of apoptotic vs clonogenic cell death to tumor cure. They also question whether apoptosis is simply another way expressing cell death. These concepts have important implications for attempts to modify the therapeutic ratio because there is little point in trying to increase apoptosis in cells already doomed to die.
Coleman and Stevenson have made important observations about radiation signal transduction, and they note that intercepting these signaling pathways may define biochemical ways to enhance radiosensitization . The authors also have made contributions to understanding the tumor microenvironment and the response to stress, especially hypoxia [4,5]. Although the role of hypoxia has been controversial in tumor radiocurability, defining steady-state vs intermittent hypoxia provides a biologic rationale for the development of hypoxic cell radiosensitizers . Uncontrolled cell proliferation in tumors has a relationship with the loss of checkpoint, control, acquisition of autocrine growth, and many other genetic changes that have direct relevance to the efficacy of radiotherapy.
In summary, the authors have successfully outlined the modern biologic basis of radiation oncology while maintaining the structure of classical radiobiologic concepts developed over the past 30 years. The fact that the authors have made major contributions to the basic aspects of radiation biology, as it applies to radiation oncology, highlights the need for more radiation oncology/basic investigators who can translate important basic biologic concepts into improvements in the therapeutic ratio in oncology.
1. Hallahan DE, Mauceri HJ, Seung LP, et al: Spatial and temporal control of gene therapy using ionizing radiation. Nature Med 1(8):786-791, 1995.
2. Huber BE, Austin EA, Richards CA, et al: Metabolism of 5-fluorocytosine to 5-fluorouracil in human colorectal tumor cells transduced with the cytosine deaminase gene: Significant antitumor effects when only a small percentage of tumor cells express cytosine deaminase. Proc Natl Acad Sci 91:8302-8306, 1994.
3. Stevenson MA, Pollock SS, Coleman CN, et al: X-irradiation, phorbol esters, and H202 stimulate mitogen-activated protein kinase activity in NIH-3T3 cells through the formation of reactive oxygen intermediates. Cancer Res 54:12-15, 1994.
4. Hlatky L, Tsionou C, Hahnfeldt P, et al: Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res 54:6083-6086, 1994.
5. Coleman CN: Radiation and chemotherapy sensitizers and protectors, in Chabner BA, Longo DL (eds): Cancer Chemotherapy. Philadelphia, JB Lippincott, 1996 (in press).