Hector Suzanne, Nava Maria Enriqueta, Clark Kimberly, Murphy Michael, Pendyala Lakshmi
Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Cancer Lett. 2007 Jan 8;245(1-2):195-204. doi: 10.1016/j.canlet.2006.01.007. Epub 2006 Mar 3.
A single cell clonal sub-line A2780/C10B that is 18-fold resistant to oxaliplatin and approximately threefold cross-resistant to cisplatin and exhibiting a metastasis associated cellular phenotype was characterized for mechanisms of resistance. The cell line exhibited a 50% reduction in the accumulation of both oxaliplatin and cisplatin relative to the parent line, while extensive decline in Pt-DNA adduct levels occurred only following oxaliplatin treatment. The basal GSH levels were fivefold higher in A2780/C10B compared to A2780 and had a fivefold elevation in gamma-GT suggesting this may be the mechanism involved in GSH elevation. The basal levels of ERCC-1, XPA and MRP-2 mRNA levels in A2780/C10B were not higher than those in A2780. The highly reduced Pt-DNA adduct formation only for oxaliplatin, but not cisplatin may be a reflection of the fact that at equimolar concentrations oxaliplatin makes fewer Pt-DNA adducts than cisplatin. The data indicate that multiple lesions occur in a single cell to produce the resistant phenotype.
对一种单细胞克隆亚系A2780/C10B进行了耐药机制研究，该亚系对奥沙利铂具有18倍耐药性，对顺铂具有约3倍交叉耐药性，并表现出与转移相关的细胞表型。相对于亲代细胞系，该细胞系中奥沙利铂和顺铂的积累量均减少了50%，而仅在奥沙利铂处理后，铂-DNA加合物水平才出现大幅下降。与A2780相比，A2780/C10B的基础谷胱甘肽（GSH）水平高5倍，γ-谷氨酰转肽酶（gamma-GT）升高5倍，提示这可能是GSH升高的相关机制。A2780/C10B中ERCC-1、XPA和MRP-2 mRNA的基础水平不高于A2780。仅奥沙利铂而非顺铂导致的铂-DNA加合物形成大幅减少，可能反映了在等摩尔浓度下，奥沙利铂形成的铂-DNA加合物比顺铂少这一事实。数据表明，单个细胞中发生多种损伤才产生耐药表型。
