PT  - JOURNAL ARTICLE
AU  - Ute Jungwirth
AU  - Dimitris N. Xanthos
AU  - Johannes Gojo
AU  - Anna K. Bytzek
AU  - Wilfried Körner
AU  - Petra Heffeter
AU  - Sergey A. Abramkin
AU  - Michael A. Jakupec
AU  - Christian G. Hartinger
AU  - Ursula Windberger
AU  - Markus Galanski
AU  - Bernhard K. Keppler
AU  - Walter Berger
TI  - Anticancer Activity of Methyl-Substituted Oxaliplatin Analogs
AID  - 10.1124/mol.111.077321
DP  - 2012 May 01
TA  - Molecular Pharmacology
PG  - 719--728
VI  - 81
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/81/5/719.short
4100  - http://molpharm.aspetjournals.org/content/81/5/719.full
SO  - Mol Pharmacol2012 May 01; 81
AB  - 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.