Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer.
Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer.
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DOI：
10.1186/1471-2407-12-15
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发表时间：
2012-01-13
期刊：
影响因子：
3.8
通讯作者：
Valette A
中科院分区：
文献类型：
--
作者：
Dufau I;Frongia C;Sicard F;Dedieu L;Cordelier P;Ausseil F;Ducommun B;Valette A
多细胞肿瘤球体（MCTS）是一种体外模型，将恶性细胞微环境和三维组织联系起来，目前在无血管肿瘤中观察到。为了评估该模型与药物联合临床前研究的相关性，我们分析了吉西他滨单独使用和与CHIR-124 CHK1抑制剂联合使用在Capan-2胰腺细胞MCTS模型中的效果。与单层培养物相比，Capan-2 MCTS表现出对吉西他滨细胞毒作用的抗性。这种耐药在egf剥夺的静止球体中被放大，这表明静止细胞在吉西他滨多细胞耐药中起作用。经长时间的吉西他滨培养后，整个球体均可见DNA损伤和大量细胞凋亡，而细胞周期阻滞仅限于细胞外层，表明吉西他滨诱导的细胞凋亡与DNA损伤直接相关。在MCTS模型中，吉西他滨联合CHIR-124增强了对吉西他滨抗增殖作用的敏感性，与DNA损伤和细胞凋亡的增加有关。这些结果表明，我们的胰腺MCTS模型适用于筛选和成像分析，是一种有价值的先进工具，用于评估药物和药物联合在化疗耐药和微环境依赖性肿瘤模型中的时空效应。
The multicellular tumor spheroid (MCTS) is an in vitro model associating malignant-cell microenvironment and 3D organization as currently observed in avascular tumors. In order to evaluate the relevance of this model for pre-clinical studies of drug combinations, we analyzed the effect of gemcitabine alone and in combination with the CHIR-124 CHK1 inhibitor in a Capan-2 pancreatic cell MCTS model. Compared to monolayer cultures, Capan-2 MCTS exhibited resistance to gemcitabine cytotoxic effect. This resistance was amplified in EGF-deprived quiescent spheroid suggesting that quiescent cells are playing a role in gemcitabine multicellular resistance. After a prolonged incubation with gemcitabine, DNA damages and massive apoptosis were observed throughout the spheroid while cell cycle arrest was restricted to the outer cell layer, indicating that gemcitabine-induced apoptosis is directly correlated to DNA damages. The combination of gemcitabine and CHIR-124 in this MCTS model, enhanced the sensitivity to the gemcitabine antiproliferative effect in correlation with an increase in DNA damage and apoptosis. These results demonstrate that our pancreatic MCTS model, suitable for both screening and imaging analysis, is a valuable advanced tool for evaluating the spatio-temporal effect of drugs and drug combinations in a chemoresistant and microenvironment-depending tumor model.
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