Abstract
Since the serendipitous discovery of cisplatin, platinum-based drugs have become well-established antitumor agents, despite the fact that their clinical use is limited by many severe side-effects. In order to both improve the chemotherapeutic index and broaden the therapeutic spectrum of current drugs, our most recent anti-neoplastic agents, Au(III) complexes, were designed as carrier-mediated delivery systems exploiting peptide transporters, which are up-regulated in some cancers. Among all, we focused on two compounds and tested them on human MDA-MB-231 (resistant to cisplatin) breast cancer cell cultures and xenografts, discovering the proteasome as a major target both in vitro and in vivo. 53% inhibition of breast tumor growth in mice was observed after 27 days of treatment at 1.0 mg kg(-1) d(-1), compared to control. Remarkably, if only the most responsive mice are taken into account, 85% growth inhibition, with some animals showing tumor shrinkage, was observed after 13 days. These results led us to file an international patent, recognizing this class of gold(III) peptidomimetics as suitable candidates for entering phase I clinical trials.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromans / pharmacology
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Cisplatin / pharmacology
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Disease Models, Animal
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Drug Design
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Drug Evaluation, Preclinical
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Female
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Free Radical Scavengers / pharmacology
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Humans
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Mice
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Molecular Structure
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Molecular Targeted Therapy
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Organogold Compounds / administration & dosage
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Organogold Compounds / chemistry
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Organogold Compounds / pharmacology*
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Peptidomimetics / administration & dosage
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Peptidomimetics / chemistry
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Peptidomimetics / pharmacology*
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors / pharmacology
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Thiocarbamates / administration & dosage
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Thiocarbamates / chemistry
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Thiocarbamates / pharmacology*
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Chromans
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Free Radical Scavengers
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Organogold Compounds
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Peptidomimetics
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Proteasome Inhibitors
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Thiocarbamates
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Proteasome Endopeptidase Complex
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Cisplatin
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6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid