Current Medicinal Chemistry - Anti-Cancer Agents, Vol. 3, No. 5, 2003
Contents
Radiation
Oncology as Mainstay of Modern Cancer Medicine
Guest
Editors: Claus Belka & Verena Jendrossek
Disruption of Cell
Death Signaling in Cancer: Impact on Disease Prognosis and Response to Therapy
Pp. 319-326
Dilek Güner , Claus Belka and Peter T. Daniel
Anti-Epidermal Growth
Factor Receptor Strategies to Enhance Radiation Action Pp. 327-333
G. Lammering
Death Receptor
Ligands: New Strategies for Combined Treatment with Ionizing Radiation Pp.
334-342
Patrizia Marini and Claus Belka
Membrane Targeted
Anticancer Drugs: Potent Inducers of Apoptosis and Putative Radiosensitisers
Pp. 343-353
V. Jendrossek and R. Handrick
New Targets for the
Modulation of Radiation Response – Selective Inhibition of the Enzyme
Cyclooxygenase 2 Pp. 354-359
Cordula Petersen ,
Michael Baumann , and Sven Petersen
Radioprotection of
K.H. Dittmann , C.
Mayer and H.P. Rodemann
Hypoxic
Radiosensitizers and Hypoxic Cytotoxins in Radiation Oncology Pp. 364-374
Martin Weinmann ,
Stefan Welz and Michael Bamberg
Antiangiogenesis and
Radiotherapy: What Is the Role of Combined Modality Treatment? Pp. 375-382
Johannes Classen and Wilfried Budach
Abstracts
[Back
to top] Disruption of Cell Death Signaling in Cancer:
Impact on Disease Prognosis and Response to Therapy
Dilek Güner , Claus
Belka and Peter T. Daniel
Disruption of cell cycle and apoptosis signaling pathways are key events during tumorigenesis, tumor progression and development of resistance against anticancer therapies. Thus, the analysis of functional alterations within these signaling cascades is of utmost importance for the understanding of resistance mechanisms, clinical outcome and risk-adapted treatment strategies. Key signaling pathways involved in the treatment resistance include the p53/p14ARF signaling complex and the mitochondrial apoptosis machinery. Apart from the direct genetic events, these signaling cascades are subject to epigenetic modulations implied by the tumor microenvironment.
[Back
to top] Anti-Epidermal Growth Factor Receptor
Strategies to Enhance Radiation Action
G. Lammering
The epidermal growth factor receptor (EGFR) has emerged as a central molecular target for modulation in cancer therapeutics, since EGFR signaling affects many factors that in turn promote tumor growth, progression and metastasis. In addition, radiobiological investigations have also defined a critical role for EGFR in mediating cytoprotective and pro-proliferative responses in human cancer cells after ionizing radiation, that contribute at least in part to accelerated tumor cell repopulation. This led to the additional development of EGFR as a target to enhance radiation efficacy. Several anti-EGFR strategies have been put forth demonstrating a favorable biological interaction between EGFR blockade and radiation. However, further preclinical investigations are necessary to better explore mechanisms of action and efficacy of combined treatment modalities. Although some of the anti-EGFR approaches have already reached clinical testing in combination with radiation, it is still too early to establish a clinical proof for the ultimate role of EGFR inhibition in combination with radiation. This article focuses primarily on anti-EGFR approaches to modulate radiation response.
[Back
to top] Death Receptor Ligands: New Strategies for
Combined Treatment with Ionizing Radiation
The major goal of modern radiation oncology is the achievement of a maximal tumor control with minimal normal tissue damage. However, normal tissue tolerance may preclude the application of tumoricidal radiation doses. In order to overcome this limitation, strategies either to increase normal tissue tolerance or to reduce the radiation dose required may prove beneficial. In this regard, attempts to minimize the required radiation dose by reducing the number of malignant clonogenic cells are promising. Therefore, therapies which induce programmed cell death (apoptosis) in tumor cells, may prove to be suitable approaches.
TRAIL (TNFa--related apoptosis inducing ligand)/Apo2L is a very promising member of the family of death ligands. The ligand preferentially induces apoptotic cell death in a wide range of tumor cells but not in normal cells. TRAIL/Apo2L triggers apoptosis even in cells not undergoing apoptosis in response to radiation, since ionizing radiation induce apoptosis by a different pathway as death ligands although an overlapping set of molecules is involved. Combination of both modalities has been shown to induce additive or synergistic apoptotic effects and eradication of clonogenic tumor cells thereby increasing the therapeutic efficacy.
The present article reviews this novel biological strategy for optimized radiotherapy based on the combination of ionizing irradiation and death receptor triggered cell death.
[Back
to top] Membrane Targeted Anticancer Drugs: Potent
Inducers of Apoptosis and Putative Radiosensitisers
V. Jendrossek and R. Handrick
In the last two decades, cellular membranes have been identified as novel targets for antineoplastic drugs. Two classes of synthetic phospholipid analogues: the alkyllysophospholipids (ALP) with the prototypical 1-O-Octadecyl-2-Omethyl- rac-glycero-3-phosphocholine (Et-18-OCH3, Edelfosine ®), as well as the alkylphosphocholines (APC) with the prototypical hexadecylphosphocholine (HePC, Miltefosine ®), have been identified targeting cellular membranes and exerting potent antineoplastic effects in cell culture and animal models. In contrast to most of the chemotherapeutic agents in clinical use, APC and ALP primarily interfere with cellular membranes without direct interaction with the DNA. They modulate membrane permeability and fluidity, membrane lipid composition, metabolism of phospholipids and proliferation signal transduction. Interestingly, similar to DNA-damaging drugs, ALP and APC induce apoptotic cell death. Furthermore, combination experiments with cytotoxic drugs or radiation revealed a synergistic effect in leukaemic and brain tumour cell lines. These findings together with the observations that ALP and APC selectively kill malignant cells, that they lack bone marrow toxicity and even exert growth stimulatory effects on hematopoietic progenitor cells make ALP and APC a promising tool for novel approaches in cancer chemotherapy. In this contribution, novel findings on the mechanism of action, apoptotic signalling pathways and putative radiosensitising effects of ALP and APC were reviewed, with a special focus on erucylphosphocholine (ErPC), the prototype of the novel intravenously applicable APC derivatives.
[Back
to top] New Targets for the Modulation of Radiation Response
– Selective Inhibition of the Enzyme Cyclooxygenase 2
Cordula
Petersen , Michael Baumann , and Sven
Petersen
The development of new chemotherapeutic agents and concepts of radiation therapy has led to new perspectives in cancer therapy. Recently developed novel agents interfere with molecular mechanisms that are altered in cancer cells. Cyclooxygenase-2 (COX-2) is an enzyme induced by a variety of factors including tumor promoters, cytokines, growth factors and hypoxia. It is involved in the metabolic conversion of arachidonic acid to prostanoids, primarily in inflammatory states and tumors. In normal tissues, prostanoids are synthesized by COX-1, and they exert numerous homeostatic physiological functions. COX-2 overexpression is linked to carcinogenesis, maintenance of progressive tumor growth and metastatic spread. COX-2 and its products may act as protectors against cell damage by ionizing radiation. In this context, the treatment with selective COX-2 inhibitors became of interest for radiation oncology within the last years. In this review we focus on the effects of COX-2 in the modulation of the radiation response and the potential clinical application as cancer preventive drug or as novel agents in adjuvant clinical settings. The experimental data available suggest that COX-2 inhibitors can enhance the radiation response in tumors without serious side effects to the normal tissue. In conclusion COX-2 might be a useful tool for cancer prevention and represents a potential molecular target for improving cancer treatment in combination with radiotherapy.
[Back
to top] Radioprotection of
K.H. Dittmann , C. Mayer and H.P. Rodemann
Specific radioprotection of normal tissue represents a promising approach to improve radiotherapy. The ultimate feature of a normal tissue selective radioprotector is that tumor tissue is excluded from protection. Radioprotectors of the current generation, such as Ethyol, are not explicit normal tissue specific. In contrast, the Bowman Birk protease inhibitor, which is known to prevent in vitro and in vivo radiation-induced carcinogenesis, was found to be normal tissue specific. Moreover, the molecular restrictions for this specificity were identified. The radioprotective effect is dependent upon the presence of a functional wt. TP53. Since a high amount of tumors have lost TP53 function during tumor development, the clinical application of BBI to protect normal tissue from radiation damage would effectively improve the therapeutic outcome of radiation therapy. We succeeded to identify stimulation of DNA-repair mechanisms, such as nucleotide excision repair (NER) and nonhomologous end joining (NHEJ), as molecular mode of action. These results are in good agreement with the observations that BBI concomitantly exhibits anticarcinogenic effect and radioprotective effects. Taken together, BBI is recommended as a radioprotector for normal tissue expressing wild type TP53 during treatment of tumors characterized by a mutant TP53.
[Back
to top] Hypoxic Radiosensitizers and Hypoxic Cytotoxins in
Radiation Oncology
Martin Weinmann , Stefan Welz and Michael Bamberg
Tumor hypoxia is a major constraint for the tumor treatment by radiotherapy. The efficacy of ionizing radiation directly relies on adequate oxygen tensions. Furthermore, hypoxia is related to malignant progression, increased invasion, angiogenesis and an increased risk of metastases formation. Two different types of strategies can be used to overcome the problem of hypoxia-mediated radioresistance. The first strategy encompasses a variety of different methods to improve the tumor oxygenation during radiotherapy. The second strategy tries to target hypoxia as a relatively unique feature of tumor tissue by means of drugs, which are activated under hypoxic conditions and act as hypoxic radiosensitizers or hypoxic cytotoxins. This article reviews in brief the clinical experience with different generations of hypoxic radiosensitizers and hypoxic cytotoxins, which have been applied in combination with primary radiotherapy during the last three decades.
[Back
to top] Antiangiogenesis and Radiotherapy: What Is the Role
of Combined Modality Treatment?
Johannes Classen and Wilfried Budach
The formation of new blood vessels is a prerequisite for the growth of primary and metastatic tumour. Thus, strategies that aim at the inhibition of tumour angiogenesis have gained considerable interest in recent years. Furthermore, there is a need to identify the role of antiangiogenic agents in conjunction with conventional anticancer modalities like chemotherapy or radiotherapy. It is the objective of this review to summarise experimental data for different antiangiogenic agents used for combined modality experiments with radiotherapy.
Promising data have been reported for a series of antiangiogenic agents for combined modality treatment with radiotherapy using tumour growth delay as the primary end-point. Yet, the results from different agents with various tumour lines are contradictory in part. Furthermore, enhancement of local tumour control, the main objective of curative radiotherapy, has so far been demonstrated for only two agents (DC101 and CA4DP), while experiments using TNP-470 even revealed a reduction of local tumour control when combined with irradiation. Finally, detailed studies investigating the modulation of normal tissue reactions for the combination of radiotherapy and inhibitors of angiogenesis are pending so far. Thus, experimental data currently available do not consistently support the beneficial effects of combined modality treatment with inhibitors of angiogenesis and radiotherapy. We therefore conclude that there is still a long way to go until we know which antiangiogenic agent will clinically be suitable for what tumour entity for combined treatment of radiotherapy and inhibitors of angiogenesis.