Current Medicinal Chemistry - Anti-Cancer Agents - Volume 3, Issue 5, 2003

(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).

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.

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.

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 (TNFα-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.

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.

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.

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.

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.

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.