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  •   Open Research
  • AUT Faculties
  • Faculty of Design and Creative Technologies (Te Ara Auaha)
  • School of Engineering, Computer and Mathematical Sciences - Te Kura Mātai Pūhanga, Rorohiko, Pāngarau
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Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

Glaysher, S; Yiannakis, D; Gabriel, FG; Johnson, P; Polak, ME; Knight, LA; Goldthorpe, Z; Peregrin, K; Gyi, M; Modi, P; Rahamim, J; Smith, ME; Amer, K; Addis, B; Poole, M; Narayanan, A; Gulliford, TJ; Andreotti, PE; Cree, IA
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http://hdl.handle.net/10292/8195
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Abstract
Background

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.

Methods

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.

Results

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.

Conclusion

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.
Keywords
Aged; Aged, 80 and over; Antineoplastic agents; Carcinoma; Non-small-cell lung; Drug resistance; Neoplasm; Drug screening assays; Antitumor; Female; Gene expression regulation; Neoplastic; Humans; Lung neoplasms; Male; Middle aged
Date
2009
Source
BMC Cancer 2009, 9:300. DOI:10.1186/1471-2407-9-300
Item Type
Journal Article
Publisher
BioMed Central
DOI
10.1186/1471-2407-9-300
Publisher's Version
http://dx.doi.org/10.1186/1471-2407-9-300
Rights Statement
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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