title: In vitro and in vivo activity and cross resistance profiles of novel ruthenium (II) organometallic arene complexes in human ovarian cancer.
abstract: Ruthenium complexes offer the potential of reduced toxicity, a novel mechanism of action, non-cross resistance and a different spectrum of activity compared to platinum containing compounds. Thirteen novel ruthenium(II) organometallic arene complexes have been evaluated for activity (in vitro and in vivo) in models of human ovarian cancer, and cross-resistance profiles established in cisplatin and multi-drug-resistant variants. A broad range of IC50 values was obtained (0.5 to >100 microM) in A2780 parental cells with two compounds (RM175 and HC29) equipotent to carboplatin (6 microM), and the most active compound (HC11) equipotent to cisplatin (0.6 microM). Stable bi-dentate chelating ligands (ethylenediamine), a more hydrophobic arene ligand (tetrahydroanthracene) and a single ligand exchange centre (chloride) were associated with increased activity. None of the six active ruthenium(II) compounds were cross-resistant in the A2780cis cell line, demonstrated to be 10-fold resistant to cisplatin/carboplatin by a mechanism involving, at least in part, silencing of MLH1 protein expression via methylation. Varying degrees of cross-resistance were observed in the P-170 glycoprotein overexpressing multi-drug-resistant cell line 2780AD that could be reversed by co-treatment with verapamil. In vivo activity was established with RM175 in the A2780 xenograft together with non-cross-resistance in the A2780cis xenograft and a lack of activity in the 2780AD xenograft. High activity coupled to non cross-resistance in cisplatin resistant models merit further development of this novel group of anticancer compounds.
authors.affiliation: Cancer Research UK, Edinburgh Oncology Unit, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK. jeffrey.cummings@cancer.org.uk
authors.forename: R E
authors.initials: RE
authors.lastname: Aird
authors.forename: J
authors.initials: J
authors.lastname: Cummings
authors.forename: A A
authors.initials: AA
authors.lastname: Ritchie
authors.forename: M
authors.initials: M
authors.lastname: Muir
authors.forename: R E
authors.initials: RE
authors.lastname: Morris
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: P J
authors.initials: PJ
authors.lastname: Sadler
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D000077209:Decitabine; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D008024:Ligands; D009363:Neoplasm Proteins; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D000077209:Decitabine; D004492:Edetic Acid; D016190:Carboplatin; D014700:Verapamil; D001374:Azacitidine; D002945:Cisplatin