title: In vitro and in vivo evaluation of ruthenium(II)-arene PTA complexes.
abstract: The antitumor activity of the organometallic ruthenium(II)-arene complexes, RuCl(2)(eta(6)-arene)(PTA), (arene = p-cymene, toluene, benzene, benzo-15-crown-5, 1-ethylbenzene-2,3-dimethylimidazolium tetrafluoroborate, ethyl benzoate, hexamethylbenzene; PTA = 1,3,5-triaza-7-phosphaadamantane), abbreviated RAPTA, has been evaluated. In vitro biological experiments demonstrate that these compounds are active toward the TS/A mouse adenocarcinoma cancer cell line whereas cytotoxicity on the HBL-100 human mammary (nontumor) cell line was not observed at concentrations up to 0.3 mM, which indicates selectivity of these ruthenium(II)-arene complexes to cancer cells. Analogues of the RAPTA compounds, in which the PTA ligand is methylated, have also been prepared, and these prove to be cytotoxic toward both cell lines. RAPTA-C and the benzene analogue RAPTA-B were selected for in vivo experiments to evaluate their anticancer and antimetastatic activity. The results show that these complexes can reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma in the absence of a corresponding action at the site of primary tumor growth. Pharmacokinetic studies of RAPTA-C indicate that ruthenium is rapidly lost from the organs and the bloodstream.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
authors.forename: Claudine
authors.initials: C
authors.lastname: Scolaro
authors.forename: Alberta
authors.initials: A
authors.lastname: Bergamo
authors.forename: Laura
authors.initials: L
authors.lastname: Brescacin
authors.forename: Riccarda
authors.initials: R
authors.lastname: Delfino
authors.forename: Moreno
authors.initials: M
authors.lastname: Cocchietto
authors.forename: Gábor
authors.initials: G
authors.lastname: Laurenczy
authors.forename: Tilmann J
authors.initials: TJ
authors.lastname: Geldbach
authors.forename: Gianni
authors.initials: G
authors.lastname: Sava
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001555:Benzene Derivatives / Q000737:chemistry*; D002021:Buffers; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012428:Ruthenium / Q000378:metabolism; D012965:Sodium Chloride; D012996:Solutions; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C501763:1,3,5-triaza-7-phosphaadamantane; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D002021:Buffers; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D012996:Solutions; D012965:Sodium Chloride; D012428:Ruthenium; D004247:DNA; C427203:calf thymus DNA; D000218:Adamantane