Marverti G, Piccinini G, Ghiaroni S, Barbieri D, Quaglino D, Moruzzi M S
Department of Biomedical Sciences, University of Modena, Italy.
Int J Cancer. 1998 Sep 25;78(1):33-40. doi: 10.1002/(sici)1097-0215(19980925)78:1<33::aid-ijc7>3.0.co;2-y.
The results presented here demonstrate that a cis-diamminedichloroplatinum(II) (DDP)-resistant human ovarian-carcinoma cell line is also cross-resistant to the spermine analogue N1,N12-bis(ethyl)spermine (BESPM). We report that C13* cells, which are approximately 20-fold resistant to DDP, similarly showed 7-fold resistance to BESPM by colony-forming assay with an IC50 value of 24.6 +/- 2 microM vs. 3.4 +/- 0.8 microM of 2008 cells. Resistance appears to be the result of many effects, such as different morphological and functional modifications of mitochondria. Furthermore, although BESPM accumulation was almost identical in sensitive and resistant cells, the intracellular polyamine pool of the 2 cell lines was differentially affected by this polyamine analogue. In fact, when spermidine (SPD) was still detectable in C13* cells, in 2008 cells it was not, and the spermine (SPM) content was always more markedly reduced in sensitive cells than in the resistant variant. The lower polyamine content of 2008 cells could be related to a higher degree of induction of spermidine/ spermine N1-acetyltransferase (SSAT) activity by BESPM in sensitive cells than in their resistant counterpart. Despite the observed cross-resistance, the combination of the 2 drugs resulted in supra-additive and synergistic effects in both cell lines, depending on concentration, as assessed by median-effect analysis of the survival data. The effectiveness of this combination was also confirmed by the increased accumulation of cells in the G2/M phase of the cell cycle in both cell lines. Taken together, these data suggest that BESPM effect on cell growth of DDP-sensitive and DDP-resistant cells involves multiple mechanisms that are differently modulated by the DDP-resistant phenotype.
此处呈现的结果表明，一种顺二氯二氨铂（II）（DDP）耐药的人卵巢癌细胞系对精胺类似物N1,N12-双（乙基）精胺（BESPM）也具有交叉耐药性。我们报告称，对DDP具有约20倍耐药性的C13细胞，通过集落形成试验同样显示出对BESPM具有7倍耐药性，其IC50值为24.6±2微摩尔，而2008细胞的IC50值为3.4±0.8微摩尔。耐药性似乎是多种效应的结果，比如线粒体不同的形态和功能改变。此外，尽管敏感细胞和耐药细胞中BESPM的蓄积几乎相同，但这种多胺类似物对这两种细胞系的细胞内多胺池的影响却有所不同。事实上，当C13细胞中仍可检测到亚精胺（SPD）时，2008细胞中却检测不到，并且敏感细胞中的精胺（SPM）含量总是比耐药变体中的减少得更明显。2008细胞中较低的多胺含量可能与BESPM在敏感细胞中比在其耐药对应物中诱导更高程度的亚精胺/精胺N1-乙酰转移酶（SSAT）活性有关。尽管观察到了交叉耐药性，但根据生存数据的中位效应分析，这两种药物的联合使用在两种细胞系中均产生了超相加和协同效应，具体取决于浓度。这种联合使用的有效性还通过两种细胞系在细胞周期G2/M期细胞蓄积的增加得到了证实。综上所述，这些数据表明BESPM对DDP敏感和DDP耐药细胞的细胞生长的影响涉及多种机制，而这些机制受到DDP耐药表型的不同调节。
