Combination of oxaliplatin and irinotecan on human colon cancer cell lines:: activity in vitro and in vivo
Combination of oxaliplatin and irinotecan on human colon cancer cell lines:: activity in vitro and in vivo
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DOI：
10.1097/00001813-200110000-00006
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发表时间：
2001-10-01
影响因子：
2.3
通讯作者：
Canal, P
中科院分区：
文献类型：
--
作者：
Guichard, S;Arnould, S;Canal, P
在一组4种人结肠癌细胞系及其对应异种移植物中研究了奥沙利铂和伊立替康的体外和体内联合给药。体外和体内实验表明，在三种细胞系（HCT-116，HCT-8和HT-29）中存在协同或相加的相互作用，而在SW-620细胞中存在拮抗作用。由于存在明显相反的相互作用，这取决于细胞系，我们进一步研究了可能参与HCT-8和SW-620细胞中两种药物之间相互作用的细胞决定因素。仅在HCT-8细胞中，伊立替康在存在伊立替康的情况下减缓了早期铂-DNA加合物修复（奥沙利铂暴露后1小时）（p=0.03，n=3）。此外，观察到核苷酸切除修复（NER）系统的两种蛋白质ERCC 1和XPA的表达减少。在SW-620细胞中没有观察到这些作用。伊立替康诱导SW-620细胞凋亡，增加聚（ADP-核糖）聚合酶（PARP）裂解（60 vs 7%基础水平）。用奥沙利铂预处理这些细胞可消除伊立替康诱导的PARP裂解增加（29%）。在HCT-8细胞中，无论药物处理如何，均观察到非常少的PARP裂解。存在伊立替康时铂-DNA加合物的持续存在可能是由于伊立替康对NER基因表达的直接影响或对拓扑异构酶I活性的间接影响。需要进行补充研究，以确定本研究中确定的细胞参数是否可以在临床水平上转化，以预测人体中奥沙利铂和伊立替康联合治疗后的临床应答。[(C)2001 Lippincott威廉姆斯& Wilkins.]。
The in vitro and in vivo combination of oxaliplatin and irinotecan was investigated in a panel of four human colon cancer cell lines and their counterpart xenografts. In vitro and in vivo experiments demonstrated a synergistic or additive interaction in three cell lines (HCT-116, HCT-8 and HT-29) and an antagonism in SW-620 cells. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in HCT-8 and SW-620 cells. Irinotecan slowed down the early platinum-DNA adducts repair (1 h after oxaliplatin exposure) in the presence of irinotecan only in HCT-8 cells (p=0.03, n=3). Moreover, a decrease of the expression of two proteins of the nucleotide excision repair (NER) system, ERCC1 and XPA, was observed. None of these effects was seen in SW-620 cells. Irinotecan induced apoptosis with an increase of poly(ADP-ribose) polymerase (PARP) cleavage in SW-620 cells (60 versus 7% basal level). Pretreatment of these cells with oxaliplatin abolished the increase in PARP cleavage induced by irinotecan (29%). In HCT-8 cells, a very little PARP cleavage was observed whatever the drug treatment. The persistence of platinum-DNA adducts in the presence of irinotecan could be due to a direct impact of irinotecan on NER gene expression or to an indirect effect on topoisomerase I activity. Complementary studies are required to determine if the cellular parameters identified in this study could be translated at the clinical level to predict clinical response after combined treatment with oxaliplatin and irinotecan in humans. [(C) 2001 Lippincott Williams & Wilkins.].