title: An in vivo highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex largely circumvents in vitro cisplatin resistance: two linkage isomers yield the same product upon reaction with 9-ethylguanine but exhibit different cytotoxic profiles.
abstract: Cytotoxicity assays of azolato-bridged dinuclear Pt(II) complexes, [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-azolato)](2+), where the azolato was pyrazolato (1), 1,2,3-triazolato-N1,N2 (2), tetrazolato-N1,N2 (3), or tetrazolato-N2,N3 (4), were performed in cisplatin-sensitive and -resistant human non-small-cell lung cancer cell lines (PC-9 and PC-14). These complexes largely circumvented the cisplatin resistance in both cell lines, with resistance factors for 1-4 in the range of 0.5-0.8 and 0.9-2.0 for PC-9 and PC-14 cells, respectively. Complex 4 exhibited approximately 10 times the cytotoxicity of 3. When 3 and 4 were reacted with 2 molar equiv. of 9-ethylguanine (9EtG), they yielded an identical product, [{cis-Pt(NH(3))(2)(9EtG-N7)}(2)(μ-tetrazolato-N1,N3)](3+), that had N1,N3 platinum coordination through a Pt(II) migration process on the tetrazolate ring. The second-order rate kinetics of these isomers were almost the same as each other and faster than those of 1 and 2. The cytotoxicity of azolato-bridged complexes, except for 3, increases as their kinetic rates in the 9EtG reaction increase.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Uemura
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Suzuki
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.forename: Masahiko
authors.initials: M
authors.lastname: Chikuma
authors.forename: Seiji
authors.initials: S
authors.lastname: Komeda
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D019281:Dimerization; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013777:Tetrazoles; D010984:Platinum; D006147:Guanine; C014542:9-ethylguanine; D002945:Cisplatin