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cDNA microarray-based identification of genes and pathways associated with oxaliplatin resistance

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Abstract

In order to identify genes whose expression is associated with resistance to the chemotherapeutic agent oxaliplatin, transcripts differentially expressed between an oxaliplatin sensitive and a stably resistant subline were compared in six independent replicates using Stanford cDNA microarrays for five cell lines. “Significance analysis of microarrays” (SAM) was used to identify genes whose expression was statistically significantly different in the sensitive versus resistant members of each cell line pair. The biochemical pathways of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database were searched to identify those pathways in which the number of SAM-identified genes exceeded the number expected. This identified four pathways in which upregulated genes were significantly associated with resistance in two of the cell line pairs, and two pathways in which the association was found in three cell line pairs. The search also identified 12 pathways in which downregulated genes were associated with resistance in two cell line pairs and one pathway in which the association reached statistical significance in three cell line pairs. Pathways identified included the ribosome pathway, the Huntington’s disease pathway that includes caspase 8, and the ATP synthesis pathways. Determination of the chromosomal location of each SAM-identified gene revealed several locales within which genes lay in close proximity, including three genes (APACD, IF-2, and REV1L) located on chromosome 2 that lie immediately adjacent to each other and were significantly upregulated in three of five cell line pairs. Biochemical pathway and chromosomal mapping of genes identified by SAM as differentially expressed in related cell line pairs points to mechanisms and chromosomal sites not previously suspected of association with the oxaliplatin-resistant phenotype.

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Abbreviations

APACD:

ATP binding protein associated with cell differentiation

IF-2:

Translation initiation factor IF2

KEGG:

Kyoto Encyclopedia of Genes and Genomes

SAM:

Significance analysis of microarrays

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Acknowledgements

The authors express their appreciation to Dr John Weinstein, Donna Pauler and John Crowley for helpful discussions and to Dr Bernard Palsson for use of the scanner. We would also like to thank Michael Fero and the staff of the Stanford Functional Genomics Facility for supplying us with the human cDNA microarrays used for this study. Supported by a grant from Sanofi-Synthelabo Inc., and in part by grants CA78648 and CA95298 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine and the Cancer Center, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0058, USA

    Goli Samimi, Gerald Manorek, James K. Breaux, Tim C. Cheng, Charles C. Berry & Stephen B. Howell

  2. Department of Genetics, Vrije Universiteit, de Boelelaan 1087, 1081, Amsterdam, The Netherlands

    Rob Castel

  3. Department of Surgery, University of California, 9500 Gilman Drive, La Jolla, San Diego, CA, 92093-0058, USA

    Gerrit Los

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  1. Goli Samimi
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  2. Gerald Manorek
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  3. Rob Castel
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  4. James K. Breaux
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  5. Tim C. Cheng
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  6. Charles C. Berry
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  7. Gerrit Los
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  8. Stephen B. Howell
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Correspondence to Stephen B. Howell.

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Samimi, G., Manorek, G., Castel, R. et al. cDNA microarray-based identification of genes and pathways associated with oxaliplatin resistance. Cancer Chemother Pharmacol 55, 1–11 (2005). https://doi.org/10.1007/s00280-004-0819-9

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  • DOI: https://doi.org/10.1007/s00280-004-0819-9

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