- Email: [email protected]
Translational research in radiotherapy – Getting closer to the bedside
Radiotherapy and Oncology 83 (2007) 217–219 www.thegreenjournal.com
Editorial
Translational research in radiotherapy – Getting closer to the bedside Jens Overgaarda,*, Michael Baumannb,c,d a
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark, bDepartment of Radiation Oncology, cOncoRay Center for Radiation Research in Oncology, and dExperimental Center, Medical Faculty and University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany
The translation of basic science into clinical application as well as the definition of research questions for the laboratory from clinical experience has gained ground in recent years. This holds true for both biological and physical translational research programs. Recent important fields for physical translational research, e.g. fully image-guided techniques, corrections for movement, adaptive radiotherapy techniques and hadron beam therapy, are well on their way into prospective clinical evaluation and eventually clinical routine. For radiobiology new knowledge about the underlying fundamentals of molecular biology has given new insight into mechanisms which is changing the platform from which traditional biological driven radiation research and biological driven clinical science have been derived. Of course, previously recognized important factors for optimizing the benefit of radiation treatment of tumors, namely knowledge and manipulation of hypoxia, tumor cell proliferation, and intrinsic radiosensitivity, still stand as the important challenge. However, our insight and ability to modify these factors has dramatically increased by integration of new biological knowledge into our field. For example we have identified new targets important for radiation responses and which at the same time are differently expressed between tumors and normal tissues. This importantly increases the potential of modifying both the response of tumors and of normal tissues to ionizing radiation, thereby opening new avenues to enhance the therapeutic ratio. Modern radiobiology has therefore become an important factor in the optimal design of new cancer treatment, and especially the interaction with more targeted therapeutic approaches has indicated that large potential gains are likely to be obtained. Another new and very important development needs to be mentioned in the context of translational science in radiation oncology. While until very recently radiobiology and medical radiation physics developed more or in parallel worlds with little interaction between the fields we observe today more and more simultaneous developments with important cross-fertilization. A good example is the enormous benefit from progress in modern imaging techniques for radiotherapy. Initially the better anatomical information
obtained from cross-sectional imaging allowed simply more precise definition of the target in question and formed the basis of more precise dose delivery. Soon, however, these new technical options were brought to their full potential by close interactions between biologist, physicists and radiation oncologists to investigate the volume effect for different tissues and organs of concern. Volume information is now fully integrated into routine clinical treatment planning and forms the basis for new basic and clinical research, e.g. on dose escalation, movement, or, very recent, biological imaging using PET and MR. All these projects again embrace the different professions from our discipline, and the whole translational spectrum from basic to clinical research. It has become generally recognized that optimal radiotherapy can only be applied if both the biological and technical dimensions are taken into consideration, and further of course are applied under necessary conditions to the patient’s actual malignant disease as well as the general condition and status of the patient. By the same token it is obvious to increase among others the more basic biological knowledge into a context from which modern radiotherapy is derived. Within Europe this has especially been achieved in connection with a number of focused meetings and workshops of which the international series of Wolfsberg Meetings and the translational ICTR meetings in Lugano have in recent years represented the leading effort. An overview of the published content from the most recent of these meetings, in Wolfsberg 2005 [1–18] and in Lugano 2006 [19–41], respectively, gives a clear indication of the nature and extent of the underlying biological science. The current issue of Radiotherapy and Oncology contains a series of papers presented at the 10th International Wolfsberg Meeting held in May 2007. The Wolfsberg Meetings have grown from a regional workshop to become a series of high-level scientific symposia which offer the best on the international scene of both biology and biologically-driven clinical radiotherapy. The setting of meetings has been the splendor of Wolfsberg Castle where both the beautiful nature and the kind hospitality and surroundings have given a superb frame for this growing success. The enormous scientific drive of the meeting closely correlates with the
0167-8140/$ - see front matter c 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.radonc.2007.06.001
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Translational research in radiotherapy
vision and enthusiasm of the organizers, under the eager leadership of Professor Hans Peter Rodemann, who have created a continuous row of successful symposia which most recently have been organized in connection with and as a part of the ESTRO activities. The format of the meetings has during the years very much followed the same recipe with a few invited high-level reviews together with some proffered papers and ample time for discussion of posters. This gives the platform for good interaction between especially young scientists who normally do not meet very well. The reach to the future of our discipline, i.e. the young talented scientists, is further supported by the Varian Juliana Denekamp Award given by ESTRO after peer-review of applications by an international jury to who already at a very stage in their career have demonstrated excellence and passion for biologically driven cancer research relevant for radiation oncology, and who show promise to assume a scientific leadership role in this field in the future. This year’s Varian Juliana Denekamp Award was given to equal parts to Dr. Marianne Koritzinski from the University of Maastricht and to Dr. Pierre Sonveaux University of Louvain (UCL) Medical School, Brussels. Many connections and research collaborations between different centers worldwide have been formed at Wolfsberg, some of them reaching into formal European and EU collaborations. This year’s program was no exception and as it has become a tradition we invited the review speakers and presenters of the tap-ranked abstracts to present their work in Radiotherapy and Oncology. The current issue of the journal contains these publications. The series of papers range from basic science to prospective clinical trials and probably more than before truly translate the basic knowledge into the clinical setting. Thereby it both underlines the strength and importance of the new biology but at the same time also points towards some of the challenges we still have in securing a proper clinical implementation. There has been a tendency to be a bit too little concerned with the latter point and many biologists tend to uncritically accept even weak indications of clinical relationships. However, there is a long way to go and it is important that the proper translation takes place in such a way that the design of early and more advanced confirmatory clinical studies is done at the highest level of quality and knowledge. A special highlight at the current Wolfsberg Meeting was a series of papers which maintained the use of preclinical evaluation of therapeutic strategies in quantitative in vivo tumor models. The use of the curative endpoint of local tumor control using tumor control dose 50% assays has always been an important translational activity in radiation biology and clearly represents an important step in our evaluation of new therapeutic strategies. It should be obvious that a preclinical testing ultimately should be performed in appropriate models and using the endpoints one wants in the clinical setting [20]. If that is local tumor control then of course the model system should apply such endpoint. Nevertheless do we unfortunately see more and more early basic studies apply tumor regression or growth delay outcome only, but the truth is, of course, that no one just wants a tumor to grow more slowly, they want it to disappear and consequently the preclinical assay must be directed towards that
function. This is even more important as the curative clinical endpoint is synonymous with killing of clonogenic cells, or to use a more current terminology: the tumor stem cells. An issue which also at the Wolfsberg Meeting became more in focus as the proper target to approach. A large part of the papers are devoted to hypoxia and its importance for tumor aggressiveness and especially response to ionizing radiation. No doubt, hypoxia is the area which during a century has fascinated radiation biologists the most and as seen from the present publications there is no end to this activity. What the current biology brings us is a more deep insight into the complexity of the tumor environment and the interaction between hypoxia per se and other factors such as low pH. This may in turn have implications for how several of the hypoxia-derived parameters function such as CA9 and as a spin-off also give indications to which markers must be useful to further derive in order to exploit the type of hypoxia which may be associated with radioresistance in human tumors. Also here we are getting closer to both the molecules and to the bedside and it is likely that we in the near future are going to see true predictive hypoxic markers which may bring the use of hypoxic modification back in the focus. Overall, both the recent Wolfsberg symposium and the papers presented here give a clear indication that modern radiobiology and its translational spin-off are in a good state and have reached a level where a continuous flow of new clinical studies is likely to be seen. * Corresponding author. Jens Overgaard, Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Bld. 5, DK-8000 Aarhus C, Denmark. E-mail address: [email protected] Received 4 June 2007; accepted 4 June 2007
References [1] Overgaard J, van der Kogel A. ESTRO-Wolfsberg a synergistic approach towards modern radiobiology. Radiother Oncol 2005;76:109–11. [2] Lobrich M, Jeggo PA. The two edges of the ATM sword: cooperation between repair and checkpoint functions. Radiother Oncol 2005;76:112–8. [3] Zgheib O, Huyen Y, DiTullio Jr RA, et al. ATM signaling and 53BP1. Radiother Oncol 2005;76:119–22. [4] Neijenhuis S, Begg AC, Vens C. Radiosensitization by a dominant negative to DNA polymerase beta is DNA polymerase beta-independent and XRCC1-dependent. Radiother Oncol 2005;76:123–8. [5] Seidler J, Durzok R, Brakebusch C, Cordes N. Interactions of the integrin subunit beta 1A with protein kinase B/Akt, pl30Cas and paxillin contribute to regulation of radiation survival. Radiother Oncol 2005;76:129–34. [6] Eriksen JG, Alsner J, Steiniche T, Overgaard J. The possible role of TP53 mutation status in the treatment of squamous cell carcinomas of the head and neck (HNSCC) with radiotherapy with different overall treatment times. Radiother Oncol 2005;76:135–42. [7] Toulany M, Dittmann K, Kruger M, Baumann M, Rodemann HP. Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 2005;76:143–50.
Editorial / Radiotherapy and Oncology 83 (2007) 217–219 [8] Eicheler W, Krause M, Hessel F, Zips D, Baumann M. Kinetics of EGFR expression during fractionated irradiation varies between different human squamous cell carcinoma lines in nude mice. Radiother Oncol 2005;76:151–6. [9] Dittmann K, Mayer C, Rodemann HP. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiother Oncol 2005;76: 157–61. [10] Krause M, Ostermann G, Petersen C, et al. Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation. Radiother Oncol 2005;76:162–7. [11] Meng AX, Jalali F, Cuddihy A, Bristow RG, et al. Hypoxia downregulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 2005;76:168–76. [12] Koritzinsky M, Seigneuric R, Magagnin MG, van den Beucken T, Lambin P, Wouters BG. The hypoxic proteome is influenced by gene-specific changes in mRNA translation. Radiother Oncol 2005;76:177–86. [13] Sørensen BS, Hao J, Overgaard J, et al. Influence of oxygen concentration and pH on expression of hypoxia induced genes. Radiother Oncol 2005;76:187–93. [14] Troost EG, Bussink J, Kaanders JH, et al. Comparison of different methods of CAIX quantification in relation to hypoxia in three human head and neck tumor lines. Radiother Oncol 2005;76:194–9. [15] Said HM, Katzer A, Flentje M, Vordermark D. Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells. Radiother Oncol 2005;76:200–5. [16] Yaromina A, Holscher T, Eicheler W, et al. Does heterogeneity of pimonidazole labelling correspond to the heterogeneity of radiation-response of FaDu human squamous cell carcinoma? Radiother Oncol 2005;76:206–12. [17] Hoogsteen IJ, Peeters WJ, Marres HA, et al. Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas. Radiother Oncol 2005;76:213–8. [18] Haydont V, Mathe D, Bourgier C, et al. Induction of CTGF by TGF-beta1 in normal and radiation enteritis human smooth muscle cells: Smad/Rho balance and therapeutic perspectives. Radiother Oncol 2005;76:219–25. [19] Bernier J, Overgaard J. Bridging gaps in translational radiation oncology. Radiother Oncol 2006;80:109–11. [20] Krause M, Zips D, Thames HD, Kummermehr J, Baumann M. Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy. Radiother Oncol 2006;80:112–22. [21] Nordsmark M, Loncaster J, Aquino-Parsons C, et al. The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study. Radiother Oncol 2006;80:123–31. [22] Fyles A, Milosevic M, Pintilie M, et al. Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006;80:132–7. [23] Durand RE, Aquino-Parsons C. The fate of hypoxic (pimonidazole-labelled) cells inhuman cervix tumours undergoing chemo-radiotherapy. Radiother Oncol 2006;80:138–42. [24] De Schutter H, Barbe B, Spaepen M, et al. Microsatellite alterations in head and neck squamous cell carcinoma and relation to expression of pimonidazole, CA IX and GLUT-1. Radiother Oncol 2006;80:143–50.
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[25] Thorwarih D, Eschmann SM, Holzner F, Paulsen F, Alber M. Combined uptake of[18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol 2006;80:151–6. [26] Troost EG, Laverman P, Kaanders JH, et al. Imaging hypoxia after oxygenation-modification: comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors. Radiother Oncol 2006;80:157–64. [27] Lukacova S, Overgaard J, Alsner J, Horsman MR. Strain and tumour specific variations in the effect of hypoxia on osteopontin levels in experimental models. Radiother Oncol 2006;80:165–71. [28] Debucquoy A, Goethals L, Geboes K, Roels S, Me Bride WH, Haustermans K. Molecular responses of rectal cancer to preoperative chemoradiation. Radiother Oncol 2006;80:172–7. [29] Eke I, Sandfort V, Mischkus A, Baumann M, Cordes N. Antiproliferative effects of EGFR tyrosine kinase inhibition and radiation-induced genotoxic injury are attenuated by adhesion to fibronectin. Radiother Oncol 2006;80:178–84. [30] Raju U, Ariga H, Koto M, et al. Improvement of esophageal adenocarcinoma cell and xenograft responses to radiation by targeting cyclin-dependent kinases. Radiother Oncol 2006;80:185–91. [31] Mason KA, Neal R, Hunter N, Ariga H, Ang K, Milas L. CpG oligodeoxynucleotides are potent enhancers of radio- and chemoresponses of murine tumors. Radiother Oncol 2006;80:192–8. [32] Handrick R, Rubel A, Faltin H, Eibl H, Belka C, Jendrossek V. Increased cytotoxicity of ionizing radiation in combination with membrane-targeted apoptosis modulators involves downregulation of protein kinase B/Akt-mediated survival-signaling. Radiother Oncol 2006;80:199–206. [33] Vink SR, Schellens JH, Beijnen JH, et al. Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours. Radiother Oncol 2006;80:207–13. [34] Wissink EH, Verbrugge I, Vink SR, et al. TRAIL enhances efficacy of radiotherapy in ap53 mutant, Bcl-2 overexpressing lymphoid malignancy. Radiother Oncol 2006;80:214–22. [35] Klokov D, MacPhail SM, Banath JP, Byrne JP, Olive PL. Phosphorylated histone H2AX in relation to cell survival in tumor cells and xenografts exposed to single and fractionated doses of X-rays. Radiother Oncol 2006;80:223–9. [36] Helland S, Johnsen H, Froyland C, et al. Radiation-induced effects on gene expression: an in vivo study on breast cancer. Radiother Oncol 2006;80:230–5. [37] Zschenker O, Borgmann K, Streichert T, Meier I, Wrona A, Dikomey E. Lymphoblastoid cell lines differing in p53 status show clear differences in basal gene expression with minor changes after irradiation. Radiother Oncol 2006;80:236–49. [38] Jaal J, Dorr W. Radiation-induced damage to mouse urothelial barrier. Radiother Oncol 2006;80:250–6. [39] Korreman SS, Pedersen AN, Josipovic M, et al. Cardiac and pulmonary complication probabilities for breast cancer patients after routine end-inspiration gated radiotherapy. Radiother Oncol 2006;80:257–62. [40] Steneker M, Lomax A, Schneider U. Intensity modulated photon and proton therapy for the treatment of head and neck tumors. Radiother Oncol 2006;80:263–7. [41] Cozzi L, Clivio A, Bauman G, et al. Comparison of advanced irradiation techniques with photons for benign intracranial tumours. Radiother Oncol 2006;80:268–73.
Editorial
Translational research in radiotherapy – Getting closer to the bedside Jens Overgaarda,*, Michael Baumannb,c,d a
Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark, bDepartment of Radiation Oncology, cOncoRay Center for Radiation Research in Oncology, and dExperimental Center, Medical Faculty and University Hospital Carl Gustav Carus, University of Technology, Dresden, Germany
The translation of basic science into clinical application as well as the definition of research questions for the laboratory from clinical experience has gained ground in recent years. This holds true for both biological and physical translational research programs. Recent important fields for physical translational research, e.g. fully image-guided techniques, corrections for movement, adaptive radiotherapy techniques and hadron beam therapy, are well on their way into prospective clinical evaluation and eventually clinical routine. For radiobiology new knowledge about the underlying fundamentals of molecular biology has given new insight into mechanisms which is changing the platform from which traditional biological driven radiation research and biological driven clinical science have been derived. Of course, previously recognized important factors for optimizing the benefit of radiation treatment of tumors, namely knowledge and manipulation of hypoxia, tumor cell proliferation, and intrinsic radiosensitivity, still stand as the important challenge. However, our insight and ability to modify these factors has dramatically increased by integration of new biological knowledge into our field. For example we have identified new targets important for radiation responses and which at the same time are differently expressed between tumors and normal tissues. This importantly increases the potential of modifying both the response of tumors and of normal tissues to ionizing radiation, thereby opening new avenues to enhance the therapeutic ratio. Modern radiobiology has therefore become an important factor in the optimal design of new cancer treatment, and especially the interaction with more targeted therapeutic approaches has indicated that large potential gains are likely to be obtained. Another new and very important development needs to be mentioned in the context of translational science in radiation oncology. While until very recently radiobiology and medical radiation physics developed more or in parallel worlds with little interaction between the fields we observe today more and more simultaneous developments with important cross-fertilization. A good example is the enormous benefit from progress in modern imaging techniques for radiotherapy. Initially the better anatomical information
obtained from cross-sectional imaging allowed simply more precise definition of the target in question and formed the basis of more precise dose delivery. Soon, however, these new technical options were brought to their full potential by close interactions between biologist, physicists and radiation oncologists to investigate the volume effect for different tissues and organs of concern. Volume information is now fully integrated into routine clinical treatment planning and forms the basis for new basic and clinical research, e.g. on dose escalation, movement, or, very recent, biological imaging using PET and MR. All these projects again embrace the different professions from our discipline, and the whole translational spectrum from basic to clinical research. It has become generally recognized that optimal radiotherapy can only be applied if both the biological and technical dimensions are taken into consideration, and further of course are applied under necessary conditions to the patient’s actual malignant disease as well as the general condition and status of the patient. By the same token it is obvious to increase among others the more basic biological knowledge into a context from which modern radiotherapy is derived. Within Europe this has especially been achieved in connection with a number of focused meetings and workshops of which the international series of Wolfsberg Meetings and the translational ICTR meetings in Lugano have in recent years represented the leading effort. An overview of the published content from the most recent of these meetings, in Wolfsberg 2005 [1–18] and in Lugano 2006 [19–41], respectively, gives a clear indication of the nature and extent of the underlying biological science. The current issue of Radiotherapy and Oncology contains a series of papers presented at the 10th International Wolfsberg Meeting held in May 2007. The Wolfsberg Meetings have grown from a regional workshop to become a series of high-level scientific symposia which offer the best on the international scene of both biology and biologically-driven clinical radiotherapy. The setting of meetings has been the splendor of Wolfsberg Castle where both the beautiful nature and the kind hospitality and surroundings have given a superb frame for this growing success. The enormous scientific drive of the meeting closely correlates with the
0167-8140/$ - see front matter c 2007 Published by Elsevier Ireland Ltd. doi:10.1016/j.radonc.2007.06.001
218
Translational research in radiotherapy
vision and enthusiasm of the organizers, under the eager leadership of Professor Hans Peter Rodemann, who have created a continuous row of successful symposia which most recently have been organized in connection with and as a part of the ESTRO activities. The format of the meetings has during the years very much followed the same recipe with a few invited high-level reviews together with some proffered papers and ample time for discussion of posters. This gives the platform for good interaction between especially young scientists who normally do not meet very well. The reach to the future of our discipline, i.e. the young talented scientists, is further supported by the Varian Juliana Denekamp Award given by ESTRO after peer-review of applications by an international jury to who already at a very stage in their career have demonstrated excellence and passion for biologically driven cancer research relevant for radiation oncology, and who show promise to assume a scientific leadership role in this field in the future. This year’s Varian Juliana Denekamp Award was given to equal parts to Dr. Marianne Koritzinski from the University of Maastricht and to Dr. Pierre Sonveaux University of Louvain (UCL) Medical School, Brussels. Many connections and research collaborations between different centers worldwide have been formed at Wolfsberg, some of them reaching into formal European and EU collaborations. This year’s program was no exception and as it has become a tradition we invited the review speakers and presenters of the tap-ranked abstracts to present their work in Radiotherapy and Oncology. The current issue of the journal contains these publications. The series of papers range from basic science to prospective clinical trials and probably more than before truly translate the basic knowledge into the clinical setting. Thereby it both underlines the strength and importance of the new biology but at the same time also points towards some of the challenges we still have in securing a proper clinical implementation. There has been a tendency to be a bit too little concerned with the latter point and many biologists tend to uncritically accept even weak indications of clinical relationships. However, there is a long way to go and it is important that the proper translation takes place in such a way that the design of early and more advanced confirmatory clinical studies is done at the highest level of quality and knowledge. A special highlight at the current Wolfsberg Meeting was a series of papers which maintained the use of preclinical evaluation of therapeutic strategies in quantitative in vivo tumor models. The use of the curative endpoint of local tumor control using tumor control dose 50% assays has always been an important translational activity in radiation biology and clearly represents an important step in our evaluation of new therapeutic strategies. It should be obvious that a preclinical testing ultimately should be performed in appropriate models and using the endpoints one wants in the clinical setting [20]. If that is local tumor control then of course the model system should apply such endpoint. Nevertheless do we unfortunately see more and more early basic studies apply tumor regression or growth delay outcome only, but the truth is, of course, that no one just wants a tumor to grow more slowly, they want it to disappear and consequently the preclinical assay must be directed towards that
function. This is even more important as the curative clinical endpoint is synonymous with killing of clonogenic cells, or to use a more current terminology: the tumor stem cells. An issue which also at the Wolfsberg Meeting became more in focus as the proper target to approach. A large part of the papers are devoted to hypoxia and its importance for tumor aggressiveness and especially response to ionizing radiation. No doubt, hypoxia is the area which during a century has fascinated radiation biologists the most and as seen from the present publications there is no end to this activity. What the current biology brings us is a more deep insight into the complexity of the tumor environment and the interaction between hypoxia per se and other factors such as low pH. This may in turn have implications for how several of the hypoxia-derived parameters function such as CA9 and as a spin-off also give indications to which markers must be useful to further derive in order to exploit the type of hypoxia which may be associated with radioresistance in human tumors. Also here we are getting closer to both the molecules and to the bedside and it is likely that we in the near future are going to see true predictive hypoxic markers which may bring the use of hypoxic modification back in the focus. Overall, both the recent Wolfsberg symposium and the papers presented here give a clear indication that modern radiobiology and its translational spin-off are in a good state and have reached a level where a continuous flow of new clinical studies is likely to be seen. * Corresponding author. Jens Overgaard, Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Bld. 5, DK-8000 Aarhus C, Denmark. E-mail address: [email protected] Received 4 June 2007; accepted 4 June 2007
References [1] Overgaard J, van der Kogel A. ESTRO-Wolfsberg a synergistic approach towards modern radiobiology. Radiother Oncol 2005;76:109–11. [2] Lobrich M, Jeggo PA. The two edges of the ATM sword: cooperation between repair and checkpoint functions. Radiother Oncol 2005;76:112–8. [3] Zgheib O, Huyen Y, DiTullio Jr RA, et al. ATM signaling and 53BP1. Radiother Oncol 2005;76:119–22. [4] Neijenhuis S, Begg AC, Vens C. Radiosensitization by a dominant negative to DNA polymerase beta is DNA polymerase beta-independent and XRCC1-dependent. Radiother Oncol 2005;76:123–8. [5] Seidler J, Durzok R, Brakebusch C, Cordes N. Interactions of the integrin subunit beta 1A with protein kinase B/Akt, pl30Cas and paxillin contribute to regulation of radiation survival. Radiother Oncol 2005;76:129–34. [6] Eriksen JG, Alsner J, Steiniche T, Overgaard J. The possible role of TP53 mutation status in the treatment of squamous cell carcinomas of the head and neck (HNSCC) with radiotherapy with different overall treatment times. Radiother Oncol 2005;76:135–42. [7] Toulany M, Dittmann K, Kruger M, Baumann M, Rodemann HP. Radioresistance of K-Ras mutated human tumor cells is mediated through EGFR-dependent activation of PI3K-AKT pathway. Radiother Oncol 2005;76:143–50.
Editorial / Radiotherapy and Oncology 83 (2007) 217–219 [8] Eicheler W, Krause M, Hessel F, Zips D, Baumann M. Kinetics of EGFR expression during fractionated irradiation varies between different human squamous cell carcinoma lines in nude mice. Radiother Oncol 2005;76:151–6. [9] Dittmann K, Mayer C, Rodemann HP. Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity. Radiother Oncol 2005;76: 157–61. [10] Krause M, Ostermann G, Petersen C, et al. Decreased repopulation as well as increased reoxygenation contribute to the improvement in local control after targeting of the EGFR by C225 during fractionated irradiation. Radiother Oncol 2005;76:162–7. [11] Meng AX, Jalali F, Cuddihy A, Bristow RG, et al. Hypoxia downregulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 2005;76:168–76. [12] Koritzinsky M, Seigneuric R, Magagnin MG, van den Beucken T, Lambin P, Wouters BG. The hypoxic proteome is influenced by gene-specific changes in mRNA translation. Radiother Oncol 2005;76:177–86. [13] Sørensen BS, Hao J, Overgaard J, et al. Influence of oxygen concentration and pH on expression of hypoxia induced genes. Radiother Oncol 2005;76:187–93. [14] Troost EG, Bussink J, Kaanders JH, et al. Comparison of different methods of CAIX quantification in relation to hypoxia in three human head and neck tumor lines. Radiother Oncol 2005;76:194–9. [15] Said HM, Katzer A, Flentje M, Vordermark D. Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells. Radiother Oncol 2005;76:200–5. [16] Yaromina A, Holscher T, Eicheler W, et al. Does heterogeneity of pimonidazole labelling correspond to the heterogeneity of radiation-response of FaDu human squamous cell carcinoma? Radiother Oncol 2005;76:206–12. [17] Hoogsteen IJ, Peeters WJ, Marres HA, et al. Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas. Radiother Oncol 2005;76:213–8. [18] Haydont V, Mathe D, Bourgier C, et al. Induction of CTGF by TGF-beta1 in normal and radiation enteritis human smooth muscle cells: Smad/Rho balance and therapeutic perspectives. Radiother Oncol 2005;76:219–25. [19] Bernier J, Overgaard J. Bridging gaps in translational radiation oncology. Radiother Oncol 2006;80:109–11. [20] Krause M, Zips D, Thames HD, Kummermehr J, Baumann M. Preclinical evaluation of molecular-targeted anticancer agents for radiotherapy. Radiother Oncol 2006;80:112–22. [21] Nordsmark M, Loncaster J, Aquino-Parsons C, et al. The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study. Radiother Oncol 2006;80:123–31. [22] Fyles A, Milosevic M, Pintilie M, et al. Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006;80:132–7. [23] Durand RE, Aquino-Parsons C. The fate of hypoxic (pimonidazole-labelled) cells inhuman cervix tumours undergoing chemo-radiotherapy. Radiother Oncol 2006;80:138–42. [24] De Schutter H, Barbe B, Spaepen M, et al. Microsatellite alterations in head and neck squamous cell carcinoma and relation to expression of pimonidazole, CA IX and GLUT-1. Radiother Oncol 2006;80:143–50.
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