Author
Walter Berger
Other affiliations: University of Vienna, Université libre de Bruxelles, VRVis
Bio: Walter Berger is an academic researcher from Medical University of Vienna. The author has contributed to research in topics: Cell culture & Prodrug. The author has an hindex of 63, co-authored 359 publications receiving 14045 citations. Previous affiliations of Walter Berger include University of Vienna & Université libre de Bruxelles.
Topics: Cell culture, Prodrug, Apoptosis, In vivo, Cell growth
Papers published on a yearly basis
Papers
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TL;DR: The experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction.
Abstract: The promising drug candidate indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) is the second Ru-based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et al., J. Inorg. Biochem. 2006, 100, 891-904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects.
691 citations
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Heidelberg University1, German Cancer Research Center2, St. Jude Children's Research Hospital3, University of Toronto4, Ontario Institute for Cancer Research5, Institute of Cancer Research6, University of California, San Francisco7, Cincinnati Children's Hospital Medical Center8, Sapienza University of Rome9, University of Warsaw10, Boston Children's Hospital11, University of Bonn12, University of Hamburg13, Medical University of Vienna14, French Institute of Health and Medical Research15, Karolinska Institutet16, University of Freiburg17, Cork University Hospital18, Hadassah Medical Center19, Otto-von-Guericke University Magdeburg20, Copenhagen University Hospital21, Vanderbilt University Medical Center22, Children's Hospital of Philadelphia23, Washington University in St. Louis24, University of Göttingen25, Augsburg College26, University of Münster27, Radboud University Nijmegen28, VU University Medical Center29, University Medical Center Freiburg30, Ludwig Maximilian University of Munich31, University of Tübingen32, University of Basel33, Masaryk University34, University of Cambridge35, University of Amsterdam36, Necker-Enfants Malades Hospital37, Institut Gustave Roussy38, Aix-Marseille University39, University of Düsseldorf40, Virginia Commonwealth University41, University of Würzburg42, New York University43, Henry Ford Hospital44, University of Texas MD Anderson Cancer Center45, University of Queensland46, McGill University47
TL;DR: It is demonstrated that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors.
648 citations
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TL;DR: Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
Abstract: NKP-1339 is the first-in-class ruthenium-based anticancer drug in clinical development against solid cancer and has recently been studied successfully in a phase I clinical trial. Ruthenium compounds such as KP1019 (indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) and NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) have a high tumour targeting potential based (1) on their strong binding to serum proteins such as albumin and transferrin as well as (2) on their activation in the reductive tumour milieu. The redox activity of ruthenium compounds is believed to represent one major mode of action leading to disturbance of the cellular redox balance and, consequently, induction of G2/M cell cycle arrest, blockage of DNA synthesis, and induction of apoptosis via the mitochondrial pathway. Moreover, potent synergistic activities of NKP-1339 with the clinically approved tyrosine kinase inhibitor sorafenib were recently reported in vitro and in vivo. Taken together, KP1019 and NKP-1339 are promising drug candidates, and especially the very limited side effects observed so far in clinical phase I trials seem to be a major advantage of this class of ruthenium drugs as compared to other chemotherapeutics and targeted anticancer compounds.
505 citations
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TL;DR: The aim of this review is to highlight specific interactions of metal-based anticancer drugs with the cellular redox homeostasis and to explain this behavior by considering chemical properties of the respective anticancer metal complexes currently either in (pre)clinical development or in daily clinical routine in oncology.
Abstract: Cells require tight regulation of the intracellular redox balance and consequently of reactive oxygen species for proper redox signaling and maintenance of metal (e.g., of iron and copper) homeostasis. In several diseases, including cancer, this balance is disturbed. Therefore, anticancer drugs targeting the redox systems, for example, glutathione and thioredoxin, have entered focus of interest. Anticancer metal complexes (platinum, gold, arsenic, ruthenium, rhodium, copper, vanadium, cobalt, manganese, gadolinium, and molybdenum) have been shown to strongly interact with or even disturb cellular redox homeostasis. In this context, especially the hypothesis of “activation by reduction” as well as the “hard and soft acids and bases” theory with respect to coordination of metal ions to cellular ligands represent important concepts to understand the molecular modes of action of anticancer metal drugs. The aim of this review is to highlight specific interactions of metal-based anticancer drugs with t...
417 citations
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TL;DR: Global structure-activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics.
Abstract: Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure–activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.
301 citations
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TL;DR: The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.
3,299 citations
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TL;DR: The anticancer effects of phenolics in-vitro and in- vivo animal models are viewed, including recent human intervention studies, and possible mechanisms of action involving antioxidant and pro-oxidant activity as well as interference with cellular functions are discussed.
Abstract: Phenolics are broadly distributed in the plant kingdom and are the most abundant secondary metabolites of plants. Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases such as cancer. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research. This review provides an updated and comprehensive overview on phenolic extraction, purification, analysis and quantification as well as their antioxidant properties. Furthermore, the anticancer effects of phenolics in-vitro and in-vivo animal models are viewed, including recent human intervention studies. Finally, possible mechanisms of action involving antioxidant and pro-oxidant activity as well as interference with cellular functions are discussed.
3,213 citations
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TL;DR: Various approaches to combating multidrug-resistant cancer are described, including the development of drugs that engage, evade or exploit efflux by ABC transporters.
Abstract: Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.
3,147 citations
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TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore
PL02-05
All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.
2,737 citations