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.
Drs. Coleman and Stevenson have done a superb job in coveringdiverse aspects of biology relevant to clinical radiotherapy.They note that recent advances in understanding DNA repair maylead to practical applications in radiotherapy. For example, adual benefit of unraveling DNA repair mechanisms may be to identifywhich tumors are the most likely to respond to therapeutic radiationand which patients are most likely to develop radiation-inducedtumors. The authors point out that gene induction observed invitro following large radiation doses may not necessarily be relevantto doses employed clinically. Coleman and Stevenson highlightthe importance of defining the sequence of genes induced by radiationin clinically relevant doses.
Since the submission of this article, Hallahan et al have reportedthat gene therapy can be spatially and temporally controlled byionizing radiation by employing radiation-inducible promoterslinked to toxins . In a broader context, gene therapy alsois likely to be combined with radiotherapy employing constitutivepromoters. One example is the use of the cytosine deaminase genein combination with the prodrug flucytosine (Ancobon) to achieveradiosensitization by conversion of flucytosine to fluorouracil.
Cell-cycle progression is likely to be another target for modifyingthe therapeutic ratio. It is of historical interest that the firstgenetically defined checkpoint, the G2 block in Saccharomycescerevisiae, was described using radiation as the prototypicalDNA-damaging agent.
Intriguing Questions About Aptosis
The authors discuss apoptosis and p53 in a concise fashion andraise an intriguing question about the relative contributionsof apoptotic vs clonogenic cell death to tumor cure. They alsoquestion whether apoptosis is simply another way expressing celldeath. These concepts have important implications for attemptsto modify the therapeutic ratio because there is little pointin trying to increase apoptosis in cells already doomed to die.
Coleman and Stevenson have made important observations about radiationsignal transduction, and they note that intercepting these signalingpathways may define biochemical ways to enhance radiosensitization. The authors also have made contributions to understandingthe tumor microenvironment and the response to stress, especiallyhypoxia [4,5]. Although the role of hypoxia has been controversialin tumor radiocurability, defining steady-state vs intermittenthypoxia provides a biologic rationale for the development of hypoxiccell radiosensitizers . Uncontrolled cell proliferation intumors has a relationship with the loss of checkpoint, control,acquisition of autocrine growth, and many other genetic changesthat have direct relevance to the efficacy of radiotherapy.
In summary, the authors have successfully outlined the modernbiologic basis of radiation oncology while maintaining the structureof classical radiobiologic concepts developed over the past 30years. The fact that the authors have made major contributionsto the basic aspects of radiation biology, as it applies to radiationoncology, highlights the need for more radiation oncology/basicinvestigators who can translate important basic biologic conceptsinto improvements in the therapeutic ratio in oncology.
1. Hallahan DE, Mauceri HJ, Seung LP, et al: Spatial and temporalcontrol 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-fluorocytosineto 5-fluorouracil in human colorectal tumor cells transduced withthe cytosine deaminase gene: Significant antitumor effects whenonly 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 kinaseactivity in NIH-3T3 cells through the formation of reactive oxygenintermediates. Cancer Res 54:12-15, 1994.
4. Hlatky L, Tsionou C, Hahnfeldt P, et al: Mammary fibroblastsmay influence breast tumor angiogenesis via hypoxia-induced vascularendothelial 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).