Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
Mol Pharmacol. 2012 May;81(5):719-28. doi: 10.1124/mol.111.077321. Epub 2012 Feb 13.
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.
奥沙利铂成功应用于全身癌症治疗。然而，耐药性的发展和严重的不良反应是限制奥沙利铂治疗癌症疗效的因素。本研究的目的是比较研究两种甲基取代的对映纯奥沙利铂类似物[[(1R,2R,4R)-4-甲基-1,2-环己二胺]草酸盐铂(II) (KP1537)和[(1R,2R,4S)-4-甲基-1,2-环己二胺]草酸盐铂(II) (KP1691)]的体外和体内抗癌特性以及不良反应，并评估立体异构体的影响。尽管新型奥沙利铂类似物在多个方面表现出与母体化合物相当的活性，但也发现了一些关键差异。这些类似物的特点是对耐药机制（如 p53 突变）的脆弱性降低，对免疫原性细胞死亡诱导的依赖性降低，以及明显减轻的不良反应，包括体重减轻和冷超敏反应。取代甲基的立体异构体对药物积累和体内外抗癌活性的影响复杂，在某些方面甚至相互矛盾。总之，甲基取代的奥沙利铂类似物具有改善的治疗特性，包括显著降低的不良反应。因此，它们可能是有前途的金属基抗癌药物候选物，值得进一步（临床前）评估。
