title: Anticancer activity of methyl-substituted oxaliplatin analogs.
abstract: Oxaliplatin is successfully used in systemic cancer therapy. However, resistance development and severe adverse effects are limiting factors for curative cancer treatment with oxaliplatin. The purpose of this study was to comparatively investigate in vitro and in vivo anticancer properties as well as the adverse effects of two methyl-substituted enantiomerically pure oxaliplatin analogs [[(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine] oxalatoplatinum(II) (KP1537), and [(1R,2R,4S)-4-methyl-1,2-cyclohexanediamine]oxalatoplatinum(II) (KP1691)] and to evaluate the impact of stereoisomerism. Although the novel oxaliplatin analogs demonstrated in multiple aspects activities comparable with those of the parental compound, several key differences were discovered. The analogs were characterized by reduced vulnerability to resistance mechanisms such as p53 mutations, reduced dependence on immunogenic cell death induction, and distinctly attenuated adverse effects including weight loss and cold hyperalgesia. Stereoisomerism of the substituted methyl group had a complex and in some aspects even contradictory impact on drug accumulation and anticancer activity both in vitro and in vivo. To summarize, methyl-substituted oxaliplatin analogs harbor improved therapeutic characteristics including significantly reduced adverse effects. Hence, they might be promising metal-based anticancer drug candidates for further (pre)clinical evaluation.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Ute
authors.initials: U
authors.lastname: Jungwirth
authors.forename: Dimitris N
authors.initials: DN
authors.lastname: Xanthos
authors.forename: Johannes
authors.initials: J
authors.lastname: Gojo
authors.forename: Anna K
authors.initials: AK
authors.lastname: Bytzek
authors.forename: Wilfried
authors.initials: W
authors.lastname: Körner
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Abramkin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
authors.forename: Ursula
authors.initials: U
authors.lastname: Windberger
authors.forename: Markus
authors.initials: M
authors.lastname: Galanski
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077150:Oxaliplatin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D004247:DNA