Schlüsselwörter
(Englisch)
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Anticancer drugs; Resistance pathways; Bioorganometallic chemistry; drug mechanisms; drug targeting
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Forschungsprogramme
(Englisch)
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COST-Action D39 - Metallo-Drug Design and Action
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Kurzbeschreibung
(Englisch)
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To design, synthesize and evaluate new ruthenium-based anticancer drugs that overcome resistance and target cancer cells. Detailed biological evaluation and mechanistic studies will be performed on the compounds.
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Weitere Hinweise und Angaben
(Englisch)
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Full name of research-institution/enterprise: Université de Lausanne Institut Universitaire de Pathologie CHUV
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Partner und Internationale Organisationen
(Englisch)
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AT, BE, CH, CZ, DE, DK, ES, FR, GR, HU, IE, IL, IT, NL, NO, PL, PT, RO, SE, SI, TR, UK
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Abstract
(Englisch)
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Cisplatin is widely used to treat cancer, however significant problems associated with cisplatin include general toxicity leading to severe side effects, and drug resistance, limiting its applicability. To overcome these limitations some progress has been made with other organometallic drugs such as agents based on ruthenium. The goals of our project are to develop multifunctional ruthenium-based organometallic chemotherapeutic agents, and combination therapies required to achieve less generalized toxicities and more efficient therapies of cancer. Such a combined strategy should offer the advantage over existing drugs by showing efficacy against cancers that are difficult to treat and reducing general toxicity. We have designed, developed and evaluated several series of compounds that have various chemical groups attached, including inhibitors of drug resistance pathways of cancer cells, mainly directed against the enzyme Glutathione-S-Transferase involved in the resistance of cancer cells to organometallics, or targeting agents for defined markers of human tumors, such as receptors for serum proteins or carbohydrate analogs, with the intention of further increasing the efficacy of these chemotherapeutics against cancer. One such innovative cancer treatment modality that we evaluated in detail, was to combine an organometallic agent with a porphyrin analogue in order to improve their uptake by cancer cells since porphyrin derivatives concentrate in cancer cells, and to combine chemotherapeutic approaches based on the ruthenium part of the molecule, with photodynamic approaches based on the photosensitizing properties of the porphyrin. Therefore complexes of several porphyrin coordinated to ruthenium were developed, and their biological effects, their cell uptake and intracellular localization were assessed in several different human cancer cells as models of human cancer. The ruthenium compounds were active in the dark due to the metal and the porphyrin part was highly effective following irradiation with laser light. Co-localization studies of the fluorescent porphyrin moiety and the metal component of the complexes localized in similar structures in the cells. They were found concentrated in the cell cytoplasm and/or organelles, different of the lysosomes or the nucleus. When exposed to laser light, they also demonstrated photodynamic efficacy. Some of these compounds were selective for cancer cells of the female reproductive system. Very recently, anthracene-ruthenium derivatives have been prepared and evaluated on a panel of human cells, providing interesting structural information. A manuscript will be submitted for publication. Several manuscripts describing these results have been published, and one patent has been obtained. These results have also been included in the PhD thesis manuscript of Frédéric Schmitt, whose part of the salary was provided by this grant. The thesis has been sucessfully defended by Frédéric Schmitt on July 9th 2009.
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Datenbankreferenzen
(Englisch)
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C06.0153
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