Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
J Biol Inorg Chem. 2012 Jun;17(5):699-708. doi: 10.1007/s00775-012-0889-9. Epub 2012 Mar 29.
The purpose of this study was to systematically investigate the relationships between reactivity, cellular accumulation, and cytotoxicity of a panel of oxaliplatin analogues with different leaving groups in human carcinoma cells. The reactivity of the complexes towards the nucleotides 2'-deoxyguanosine 5'-monophosphate and 2'-deoxyadenosine 5'-monophosphate was studied using capillary electrophoresis. Cellular accumulation and cytotoxicity were measured in an oxaliplatin-sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cell line pair (HCT-8/HCT-8ox). Platinum concentrations were determined by flameless atomic absorption spectrometry. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to assess cytotoxicity. Early cellular platinum accumulation was predominantly affected by lipophilicity. A relationship between reactivity and cellular accumulation was observed for three of four platinum complexes investigated, whereas the most lipophilic oxaliplatin analogue was an exception. Increased reactivity and reduced lipophilicity were associated with high cytotoxic activity. Resistance was influenced by lipophilicity but not by reactivity. The observed relationships may help in the design of analogues with high antitumoral activity in oxaliplatin-sensitive as well as oxaliplatin-resistant cells.
本研究旨在系统地研究一组具有不同离去基团的奥沙利铂类似物在人类癌细胞中的反应性、细胞内积累和细胞毒性之间的关系。使用毛细管电泳研究了配合物对核苷酸 2'-脱氧鸟苷 5'-单磷酸和 2'-脱氧腺苷 5'-单磷酸的反应性。在奥沙利铂敏感和奥沙利铂耐药回盲结直肠腺癌细胞系对（HCT-8/HCT-8ox）中测量了细胞内积累和细胞毒性。通过无火焰原子吸收光谱法测定了铂浓度。使用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基-2H-四唑溴盐（MTT）测定法评估细胞毒性。早期细胞内铂积累主要受亲脂性影响。对于研究的四种铂配合物中的三种，观察到反应性和细胞内积累之间存在关系，而最亲脂性的奥沙利铂类似物是一个例外。增加的反应性和降低的亲脂性与高细胞毒性活性相关。耐药性受亲脂性影响，但不受反应性影响。观察到的关系可能有助于设计在奥沙利铂敏感和奥沙利铂耐药细胞中具有高抗肿瘤活性的类似物。
