Preface [ Hot Topic: Radiation Oncology as Mainstay of Modern Cancer Medicine (Guest Editors: Claus Belka & Verena Jendrossek)]

(For author photo please see the pdf) Modern cancer research strongly helped to understand much of the cellular and molecular basis of cancer pathogenesis and the delineation of potential resistance pathways (see article by D. Guner in this issue). Unfortunately, up to now there was only a limited success to convert this knowledge into new and effective treatment approaches. The introduction of more or less specific kinase inhibitors like STI571/Imatinib which proved to be extremely effective as single agent in patients with CML and gastrointestinal stroma tumors remains an exception rather than a rule. During the last decade most of the advances in the treatment of cancer were based on a steady refinement of treatment procedures which are sometimes considered to be more or less “old fashioned”. Surgical and radiation based strategies in combination with adjuvant or neoadjuvant chemotherapy and hormone ablative measures remain to be the mainstay of current oncology. When major cancer entities are analyzed regarding the recommended use of the above mentioned treatment modalities it becomes clear that most actual treatment protocols are based on a complex integration of more or less all modalities (Table 1). It is evident that to date radiotherapy constitutes an integral part of merely all treatment protocols which are used in curative intent. Table 1. Role of radiotherapy within complex cancer treatment protocols. (For table please see the pdf) Nevertheless, the treatment outcomes for many entities leave much room for improvements. The current approach for treatment optimization in radiation oncology mainly focuses on dose escalation in conjunction with technological improvements of treatment delivery. However, due to the finite normal tissue tolerances it is obvious that dose escalation based strategies will have only a limited benefit. Therefore, other strategies focus on the modulation of the intrinsic radiation response, the deletion of clonogenic tumor cells by non cross resistant death mechanisms or the specific protection of the normal tissue. Up to now, most approaches have to be considered as experimental. Nevertheless, it becomes increasingly clear that novel and more specific agents will become part of clinical treatment protocols. Regarding the optimization of radiotherapy several biological targets have been identified and are reviewed in this issue of “';Current Medicinal Chemistry Anti- Cancer Agents”. The overexpression of growth factor receptors including the EGF receptors is a common finding in many tumor systems and is associated with increased radiation resistance. The article by G. Lammering in this issue reviews the role of EGF receptors for the modulation of radiation resistance and introduces novel strategies to overcome EGF-R based radiation resistance. The comparison of molecular pathways involved in the regulation of programmed death led to the observation that death receptor signaling and radiation activate cell death via distinct and not cross resistant pathways. The article by P. Marini reviews strategies based on the combination of ionizing radiation with death ligands (TRAIL). In search of further not cross resistant death pathways cellular membranes have been identified as novel targets for antineoplastic drugs. The review of V. Jendrossek introduces synthetic phospholipid derivatives as anticancer agents inducing cell death via mitochondrial signaling pathways. Their putative radiosensitizing effects as well as the lack of bone marrow toxicity make these drugs a promising tool for novel approaches in cancer therapy. A very promising approach is based on the inhibition of the Cox-2 enzyme which is more or less specifically expressed in neoplastic tissues or during inflammatory responses. A key observation was the finding that the inhibition of Cox-2 increases the radiation sensitivity of tumor but not of normal tissues (see article by C. Petersen in this issue). Since several Cox-2 inhibitors are already available and in use in clinical settings it is to be expected that the results of clinical trials on the combination of Cox-2 inhibitors with radiation will be at hand soon. A completely different approach was tested by K. Dittmann and co-workers. Using the Bowman-Birk-Proteinase (BBI) inhibitor, they could show that normal tissues expressing p53 are protected against ionizing radiation while p53 negative tumor cell systems are not. Thus, the therapeutic gain is increase by a specific modulation of the normal tissue response. The efficacy of any radiation procedure is influenced by the tumor microenvironment. Therefore, several approaches tested in how far the negative influence of hypoxia could be counteracted (see article by M. Weinmann in this issue). Alternatively, attempts were undertaken to target the vasculature in combination with radiotherapy (see article by J. Classen in this issue).