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Open Access Highly Accessed Research

Distinct genetic alterations occur in ovarian tumor cells selected for combined resistance to carboplatin and docetaxel

Stephen R Armstrong1, Rashmi Narendrula1, Baoqing Guo2, Amadeo M Parissenti123, Katherine L McCallum3, Stephanie Cull2 and Carita Lannér134*

Author Affiliations

1 Dept. of Biology, Laurentian University, Sudbury, ON, P3E2C6, Canada

2 Sudbury Regional Cancer Center, Cancer Research Laboratory, Sudbury, ON, P3E5JI, Canada

3 Division of Medical Sciences, Northern Ontario School of Medicine, Laurentian University campus, Sudbury, ON, P3E2C6, Canada

4 Northern Ontario School of Medicine, 935 Ramsey Lake Road, Sudbury, ON, P3E2C6, Canada

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Journal of Ovarian Research 2012, 5:40  doi:10.1186/1757-2215-5-40

Published: 30 November 2012

Abstract

Background

Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop and characterize a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line) and to compare this cell line to cells resistant to either carboplatin or docetaxel.

Methods

The A2780 epithelial endometrioid ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis. Changes in the expression of selected genes were validated by Quantitative Real-Time Polymerase Chain Reaction (QPCR) and immunoblotting.

Results

Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines.

Conclusions

Ovarian tumor cells can acquire resistance to both carboplatin and docetaxel when selected in the presence of both agents. Distinct changes in gene expression occur in the dual resistant cell line indicating that dual resistance is not a simple combination of the changes observed in cell lines exhibiting single agent resistance.

Keywords:
Ovarian cancer; Multidrug resistance; Carboplatin; Docetaxel; Microarray analysis; A2780 cell line