Anticancer activity of methyl-substituted oxaliplatin analogs.
Anticancer activity of methyl-substituted oxaliplatin analogs.
复制标题
DOI：
10.1124/mol.111.077321
复制
发表时间：
2012-05
影响因子：
3.6
通讯作者：
Berger W
中科院分区：
文献类型：
--
作者：
Jungwirth U;Xanthos DN;Gojo J;Bytzek AK;Körner W;Heffeter P;Abramkin SA;Jakupec MA;Hartinger CG;Windberger U;Galanski M;Keppler BK;Berger W
奥沙利铂已成功用于全身性癌症治疗。然而，耐药性发展和严重不良反应是奥沙利铂治愈性癌症治疗的限制因素。本研究的目的是比较研究两种甲基取代的对映体纯奥沙利铂类似物的体外和体内抗癌特性以及不良反应[[（1 R，2 R，4 R）-4-甲基-1，2-环己二胺]二氢合铂（II）（KP 1537），和[（1 R，2 R，4S）-4-甲基-1，2-环己二胺]亚铂（II）（KP 1691）]，并评价立体异构的影响。尽管新的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，但发现了几个关键差异。类似物的特征在于对抗性机制如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，以及明显减弱的不良反应，包括体重减轻和冷痛觉过敏。取代甲基的立体异构对药物蓄积和体内外抗癌活性具有复杂的甚至在某些方面矛盾的影响。总而言之，甲基取代的奥沙利铂类似物具有改善的治疗特征，包括显着减少的不良反应。因此，他们可能是有前途的金属为基础的抗癌药物候选人进一步（预）临床评价。
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.
登录
查看更多内容
影响因子：
6.6
作者：
Jungwirth U;Kowol CR;Keppler BK;Hartinger CG;Berger W;Heffeter P
通讯作者：
Heffeter P
影响因子：
7.4
作者：
Nassini, Romina;Gees, Maarten;Geppetti, Pierangelo
通讯作者：
Geppetti, Pierangelo
影响因子：
5
作者：
Adelsberger, H;Quasthoff, S;Lersch, C
通讯作者：
Lersch, C
影响因子：
2.9
作者：
Rappel, C;Galanski, M;Keppler, BK
通讯作者：
Keppler, BK
影响因子：
3.9
作者：
Pizarro, Ana M.;Sadler, Peter J.
通讯作者：
Sadler, Peter J.