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Open Access Highly Accessed Research article

Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer

Isabelle Dufau1*, Céline Frongia2, Flavie Sicard4, Laure Dedieu1, Pierre Cordelier4, Frédéric Ausseil1, Bernard Ducommun23 and Annie Valette2

Author Affiliations

1 USR 3388 CNRS/Pierre Fabre, Centre de Recherche et Développement Pierre Fabre, 3 avenue Hubert Curien BP 13562, 31035 Toulouse Cedex1, France

2 Université de Toulouse and CNRS, ITAV-UMS3039, Toulouse, France

3 CHU de Toulouse, Toulouse, France

4 INSERM and Université de Toulouse, CRCT-UMR1037, Toulouse, France

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BMC Cancer 2012, 12:15  doi:10.1186/1471-2407-12-15

Published: 13 January 2012

Abstract

Background

The multicellular tumor spheroid (MCTS) is an in vitro model associating malignant-cell microenvironment and 3D organization as currently observed in avascular tumors.

Methods

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.

Results

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.

Conclusions

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.

Keywords:
Tumor spheroid; Combination; Gemcitabine; CHK1 inhibitor; Pancreatic cancer