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1

Caspases - their role in apoptosis and other physiological processes as revealed by knock-out studies

100%
Sadowski-Debbing K., Coy J. F., Mier W., Hug H., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2002
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vol. 50
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issue 1
19-34
EN
Caspases are crucial mediators of apoptosis, a form of physiological cell death. Their activation is carefully controlled by a philogenetically conserved death program, which is indispensable for the homeostasis and development of higher organisms. Dysregulation of apoptosis contributes to the pathogenesis of many human diseases. As effectors of the apoptotic machinery, caspases are considered potential therapeutic targets. In vitro studies have demonstrated the requirement of caspases activity for both the triggering phase as well as the execution of apoptosis, thus providing a molecular base for the fine-tuning of this process by pharmacological agents. The precise roles of the individual caspases in vivo and their functional relation to each other have been best demonstrated in genetically modified animals. The generation of single caspase-deficient mice have confirmed most of the data obtained in vitro and exposed some new aspects previously undetected in the cell culture system. Interestingly, inactivation of many caspases revealed not only their expected participation in apoptotic events as well as in the maturation of cytokine, but also provided hints about the role of at least some caspases in cell differentation and stimulatory repsonses. In this review we will discuss what these studies have unveiled about the role of individual caspases in development, apoptosis, and inflammation, with particular focus on their role beyond the apoptotic process.
2

Anti-tumor chemotherapy utilizing peptide-based approaches ? apoptotic pathways, kinases, and proteasome as targets

86%
Mendoza F. J., Espino P. S., Cann K. L., Bristow N., Mc_Crea K., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2005
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vol. 53
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issue 1
47-60
EN
The pharmacological sciences are taking advantage of recent discoveries that have defined the molecular pathways governing apoptosis. These signaling cascades are frequently inactivated or distorted by mutations in cancer cells. Peptides derived from critical interaction, phosphorylation, or cleavage sites are the preferred leads (starting points) for the development of new drugs. In this review we summarize recent peptide-based approaches that target MDM2, p53, NF-?B, ErbB2, MAPK, as well as Smac/DIABLO, IAP BIR domains, and Bcl-2 interaction domains, with a specific focus on the BH3 domain. Separate parts of the review deal with proteasome inhibitors, integrin-derived peptides, and molecules that are being tested for tumor-selective delivery of anticancer drugs ('magic bullet' approach). The proteasome inhibitors and integrin-derived peptides show a variety of effects, targeting not only tumor growth, but also angiogenesis, metastasizing potential, and other cancer cell functions. The last part of this review describes approaches that use specific properties (surface receptors, increased enzymatic activities) of cancer cells in order to target them specifically. These new generations of anticancer drugs provide the foundations for therapies with fewer side effects and higher efficacy.
3

Bacteriophage contamination: is there a simple method to reduce its deleterious effects in laboratory cultures and biotechnological factories?

86%
Los M., Czyz A., Sell E., Wegrzyn A., Neubauer P., Wegrzyn G.
Journal of Applied Genetics
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2004
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vol. 45
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issue 1
111-120
EN
Infection of bacterial cultures by bacteriophages as well as prophage induction in the host cells are serious problems in both research and biotechnological laboratories. Generally, prevention strategies (like good laboratory/factory hygiene, sterilisation, decontamination and disinfection) are necessary to avoid bacteriophage contamination. However, it is well known that no matter how good the laboratory/factory practice and hygiene are, bacteriophage infections occur from time to time. The use of immunised or resistant bacterial strains against specific phages may be helpful, but properties of the genetically modified strains resistant to phages are often worse (from the point of view of a researcher or a biotechnological company) than those of the parental, phage-sensitive strains. In this article we review recent results that may provide a simple way to minimise deleterious effects of bacteriophage infection and prophage induction. It appears that low bacterial growth rates result in a significant inhibition of lytic development of various bacteriophages. Moreover, spontaneous prophage induction is less frequent in slowly growing bacteria.
4

Selected technologies to control genes and their products for experimental and clinical purposes

86%
Alexander H. K., Booy E. P., Xiao W., Ezzati P., Baust H., Los M.
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2007
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vol. 55
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issue 3
139-149
EN
'On-demand' regulation of gene expression is a powerful tool to elucidate the functions of proteins and biologically-active RNAs. We describe here three different approaches to the regulation of expression or activity of genes or proteins. Promoter-based regulation of gene expression was among the most rapidly developing techniques in the 1980s and 1990s. Here we provide basic information and also some characteristics of the metallothionein-promoter-based system, the tet-off system, Muristerone-A-regulated expression through the ecdysone response element, RheoSwitch?, coumermycin/novobiocin-regulated gene expression, chemical dimerizer-based promoter activation systems, the 'Dual Drug Control' system, 'constitutive androstane receptor'-based regulation of gene expression, and RU486/mifepristone-driven regulation of promoter activity. A large part of the review concentrates on the principles and usage of various RNA interference techniques (RNAi: siRNA, shRNA, and miRNA-based methods). Finally, the last part of the review deals with historically the oldest, but still widely used, methods of temperature-dependent regulation of enzymatic activity or protein stability (temperature-sensitive mutants). Due to space limitations we do not describe in detail but just mention the tet-regulated systems and also fusion-protein-based regulation of protein activity, such as estrogen-receptor fusion proteins. The information provided below is aimed to assist researchers in choosing the most appropriate method for the planned development of experimental systems with regulated expression or activity of studied proteins.
5

Viral modulation of cell death by inhibition of caspases

86%
Cassens U., Lewinski G., Samraj A. K., von_ B. H., Baust H., Khazaie K., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2003
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vol. 51
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issue 1
19-27
EN
Caspases are key effectors of the apoptotic process. Some of them play an important role in the immune system, being involved in proteolytic maturation of the key cytokines including interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). The latter directs the production of interferon gamma (IFN-gamma). Among pathogens, particularly viruses express various modulators of caspases that inhibit their activity by direct binding. By evading the apoptotic process viruses can better control their production in the infected cell, and avoid the attack of immune system. Targeting of the maturation of the key cytokines involved in the initiation of (antiviral) immune response helps to avoid the recognition and eradication by the immune system. The three main classes of caspase inhibitors frequently found among viruses include serpins (CrmA/SPI-2), viral IAPs (vIAPs) and p35. Their molecular mechanism of action, structure and the overall influence on cellular physiology is discussed in the review below.
6

Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system

86%
Hauff K., Zamzow C., Law W. J., De_Melo J., Kennedy K., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2005
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vol. 53
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issue 4
308-320
EN
In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an anti-beta chain antibody 'BION-1', are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the 'blood-brain barrier' by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase-1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.
7

Stroke, myocardial infarction, acute and chronic inflammatory diseases: caspases and other apoptotic molecules as targets for drug development

73%
Kreuter M., Langer C., Kerkhoff C., Reddanna P., Kania A. L., Maddika S., Chlichlia C., Bui T. N., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2004
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vol. 52
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issue 3
141-155
EN
Mapping of the human and other eukaryotic genomes has provided the pharmacological industry with excellent models for drug discovery. Control of cell proliferation, differentiation, activation and cell removal is crucial for the development and existence of multicellular organisms. Each cell cycle progression, with sequences of DNA replication, mitosis, and cell division, is a tightly controlled and complicated process that, when deregulated, may become dangerous not only to a single cell, but also to the whole organism. Regulation and the proper control of the cell cycle and of programmed cell death (apoptosis) is therefore essential for mammalian development and the homeostasis of the immune system. The molecular networks that regulate these processes are critical targets for drug development, gene therapy, and metabolic engineering. In addition to the primary, intracellular apoptotic suicide machinery, components of the immune system can detect and remove cells and tissue fragments that no longer serve their defined functions. In this review we will focus on apoptotic pathways converging on caspase family proteases, summarizing pharmacological attempts that target genes, proteins, and intermolecular interactions capable of modulating apoptosis and the inflammatory response. The upcoming pharmacological development for treatment of acute pathologies, such as sepsis, SIRS, stroke, traumatic brain injury, myocardial infarction, spinal cord injury, acute liver failure, as well as chronic disorders such as Huntington's disease, Parkinson's disease, ALS, and rheumatoid arthritis, will be discussed in details. We also suggest new potential molecular targets that may prove to be effective in controlling apoptosis and the immune response in vivo.
8

Monoclonal and bispecific antibodies as novel therapeutics

59%
Booy E. P., Johar D., Maddika S., Pirzada H., Sahib M. M., Gehrke I., Loewen S., Louis S. F., Kadkhoda K., Mowat M., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2006
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vol. 54
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issue 2
85-101
EN
Gene amplification, over-expression, and mutation of growth factors, or the receptors themselves, causes increased signaling through receptor kinases, which has been implicated in many human cancers and is associated with poor prognosis. Tumor growth has been shown to be decreased by interrupting this process of extensive growth factor-mediated signaling by directly targeting either the surface receptor or the ligand and thereby preventing cell survival and promoting apoptosis. Monoclonal antibodies have long been eyed as a potential new class of therapeutics targeting cancer and other diseases. Antibody-based therapy initially entered clinical practice when trastuzumab/Herceptin became the first clinically approved drug against an oncogene product as a well-established blocking reagent for tumors with hyperactivity of epidermal growth factor signaling pathways. In the first part of this review we explain basic terms related to the development of antibody-based drugs, give a brief historic perspective of the field, and also touch on topics such as the 'humanization of antibodies' or creation of hybrid antibodies. The second part of the review gives an overview of the clinical usage of bispecific antibodies and antibodies 'armed' with cytotoxic agents or enzymes. Further within this section, cancer-specific, site-specific, or signaling pathway-specific therapies are discussed in detail. Among other antibody-based therapeutic products, we discuss: Avastin (bevacizumab), CG76030, Theragyn (pemtumomab), daclizumab (Zenapax), TriAb, MDX-210, Herceptin (trastuzumab), panitumumab (ABX-EGF), mastuzimab (EMD-72000), Erbitux (certuximab, IMC225), Panorex (edrecolomab), STI571, CeaVac, Campath (alemtuizumab), Mylotarg (gemtuzumab, ozogamicin), and many others. The end of the review deliberates upon potential problems associated with cancer immunotherapy.
9

Cancer stem cells as targets for cancer therapy: Selected cancers as examples

59%
Hombach-Klonisch S., Paranjothy T., Wiechec E., Pocar P., Mustafa T., Seifert A., Zahl C., Gerlach K. L., Biermann K., Steger K., Hoang-Vu C., Schulze-Osthoff K., Los M.
Archivum Immunologiae et Therapiae Experimentalis
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2008
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vol. 56
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issue 3
165-180
EN
It is becoming increasingly evident that cancer constitutes a group of diseases involving altered stem-cell maturation/differentiation and the disturbance of regenerative processes. The observed malignant transformation is merely a symptom of normal differentiation processes gone astray rather than the primary event. This review focuses on the role of cancer stem cells (CSCs) in three common but also relatively under-investigated cancers: head and neck, ovarian, and testicular cancer. For didactic purpose, the physiology of stem cells is first introduced using hematopoietic and mesenchymal stem cells as examples. This is followed by a discussion of the (possible) role of CSCs in head and neck, ovarian, and testicular cancer. Aside from basic information about the pathophysiology of these cancers, current research results focused on the discovery of molecular markers specific to these cancers are also discussed. The last part of the review is largely dedicated to signaling pathways active within various normal and CSC types (e.g. Nanog, Nestin, Notch1, Notch2, Oct3 and 4, Wnt). Different elements of these pathways are also discussed in the context of therapeutic opportunities for the development of targeted therapies aimed at CSCs. Finally, alternative targeted anticancer therapies arising from recently identified molecules with cancer-(semi-)selective capabilities (e.g. apoptin, Brevinin-2R) are considered.
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