title: Cellular transport mechanisms of cytotoxic metallodrugs: an overview beyond cisplatin.
abstract: The field of medicinal inorganic chemistry has grown consistently during the past 50 years; however, metal-containing coordination compounds represent only a minor proportion of drugs currently on the market, indicating that research in this area has not yet been thoroughly realized. Although platinum-based drugs as cancer chemotherapeutic agents have been widely studied, exact knowledge of the mechanisms governing their accumulation in cells is still lacking. However, evidence suggests active uptake and efflux mechanisms are involved; this may be involved also in other experimental metal coordination and organometallic compounds with promising antitumor activities in vitro and in vivo, such as ruthenium and gold compounds. Such knowledge would be necessary to elucidate the balance between activity and toxicity profiles of metal compounds. In this review, we present an overview of the information available on the cellular accumulation of Pt compounds from in vitro, in vivo and clinical studies, as well as a summary of reports on the possible accumulation mechanisms for different families of experimental anticancer metal complexes (e.g., Ru Au and Ir). Finally, we discuss the need for rationalization of the investigational approaches available to study metallodrug cellular transport.
authors.affiliation: Dept. Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Spreckelmeyer
authors.affiliation: Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T1Z1, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Orvig
authors.affiliation: Dept. Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands. a.casini@rug.nl.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D001692:Biological Transport; D002412:Cations / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity; D056831:Coordination Complexes / Q000378:metabolism* / Q000633:toxicity; D003300:Copper / Q000378:metabolism; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000378:metabolism* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D056831:Coordination Complexes; D026901:Membrane Transport Proteins; D009942:Organometallic Compounds; D003300:Copper; D002945:Cisplatin