TY - JOUR T1 - Reversion of Structure-Activity Relationships of Antitumor Platinum Complexes by Acetoxime but Not Hydroxylamine Ligands JF - Molecular Pharmacology JO - Mol Pharmacol SP - 357 LP - 365 DO - 10.1124/mol.106.030726 VL - 71 IS - 1 AU - Stefanie Zorbas-Seifried AU - Michael A. Jakupec AU - Nikolay V. Kukushkin AU - Michael Groessl AU - Christian G. Hartinger AU - Olga Semenova AU - Haralabos Zorbas AU - Vadim Yu. Kukushkin AU - Bernhard K. Keppler Y1 - 2007/01/01 UR - http://molpharm.aspetjournals.org/content/71/1/357.abstract N2 - The presence of cis-configured exchangeable ligands has long been considered a prerequisite for antitumor activity of platinum complexes, but over the past few years, several examples violating this structure-activity relationship have been recognized. We report here on studies with the geometric isomers of [PtCl2(acetoxime)2], cis-[dichlorobis(acetoxime)platinum(II)] [1 (cis)] and trans-[dichlorobis(acetoxime)platinum(II)] [2 (trans)], as well as those of [PtCl2(hydroxylamine)2], cis-[dichlorobis(hydroxylamine)platinum(II)] [3 (cis)] and trans-[dichlorobis(hydroxylamine)platinum(II)] [4 (trans)]. We found that 2 (trans)is 16 times more cytotoxic than 1 (cis) and as cytotoxic as cisplatin in cisplatin-sensitive ovarian carcinoma cells (CH1). Moreover, 2 (trans) is 15 times more cytotoxic than either cisplatin or 1 (cis) in intrinsically cisplatin-resistant colon carcinoma cells (SW480). Thus, compound 2 (trans) represents a novel type of active platinum(II) complexes of the trans geometry, whereas the hydroxylamine-containing complexes conform to the classic structure-activity relationships. The reactivity of the compounds toward dGMP and DNA and their capacity to alter the structure of double-stranded DNA and form interstrand cross-links were studied by capillary electrophoresis and gel electrophoresis. The slow binding of 2 (trans) to dGMP (τ½ = 50 h versus 8.9 h in the case of cisplatin), the low reactivity toward DNA, the comparatively small impact on DNA secondary structure, and the lack of detectable interstrand cross-linking suggest a mode of action fundamentally different from that of cisplatin. Implications of our findings for the minimal structural requirements (e.g., planarity around the nitrogen donor atom and/or ramified aliphatic moiety attached to the latter) of active trans-configured platinum complexes are discussed. The American Society for Pharmacology and Experimental Therapeutics ER -