Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)
Glaysher, Sharon, Yiannakis, Dennis, Gabriel, Francis G., Johnson, Penny, Polak, Marta E., Knight, Louise A., Goldthorpe, Zoe, Peregrin, Katharine, Gyi, Mya, Modi, Paul, Rahamim, Joe, Smith, Mark E., Amer, Khalil, Addis, B. J. (Bruce J.), Poole, Matthew, Narayanan, Ajit, Gulliford, Tim J., Andreotti, Peter Eugene, 1951- and Cree, Ian A.. (2009) Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC). BMC Cancer, Vol.9 (No.1). p. 300. ISSN 1471-2407
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Official URL: http://dx.doi.org/10.1186/1471-2407-9-300
NSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors.
The chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue.
There was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents.
Genes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.
|Item Type:||Journal Article|
|Subjects:||Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
|Divisions:||Faculty of Medicine > Warwick Medical School > Reproductive Health|
|Library of Congress Subject Headings (LCSH):||Lungs -- Cancer -- Treatment, Drug resistance in cancer cells -- Genetic aspects|
|Journal or Publication Title:||BMC Cancer|
|Publisher:||BioMed Central Ltd.|
|Official Date:||27 August 2009|
|Page Range:||p. 300|
|Access rights to Published version:||Open Access|
|Funder:||CanTech Ltd., Sanofi Aventis (Firm)|
1. Fossella FV, DeVore R, Kerr RN, Crawford J, Natale RR, Dunphy F,
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