Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer

Cancer Res. 2006 Mar 1;66(5):2765-77. doi: 10.1158/0008-5472.CAN-05-2693.

Abstract

DNA microarray analysis was used to analyze the transcriptional profile of HCT116 colorectal cancer cells that were treated with 5-fluorouracil (5-FU) or oxaliplatin and selected for resistance to these agents. Bioinformatic analyses identified sets of genes that were constitutively dysregulated in drug-resistant cells and transiently altered following acute exposure of parental cells to drug. We propose that these genes may represent molecular signatures of sensitivity to 5-FU and oxaliplatin. Using real-time reverse transcription-PCR (RT-PCR), the robustness of our microarray data was shown with a strong overall concordance of expression trends for > or =82% (oxaliplatin) and > or =85% (5-FU) of a representative subset of genes. Furthermore, strong correlations between the microarray and real-time RT-PCR measurements of average fold changes in gene expression were observed for both the 5-FU (R(2) > or = 0.73) and oxaliplatin gene sets (R(2) > or = 0.63). Functional analysis of three genes identified in the microarray study [prostate-derived factor (PDF), calretinin, and spermidine/spermine N(1)-acetyl transferase (SSAT)] revealed their importance as novel regulators of cytotoxic drug response. These data show the power of this novel microarray-based approach to identify genes which may be important markers of response to treatment and/or targets for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Drug Resistance, Neoplasm / genetics
  • Fluorouracil / pharmacology*
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • HCT116 Cells
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • Pharmacogenetics
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Transfection

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • RNA, Messenger
  • RNA, Small Interfering
  • Oxaliplatin
  • Fluorouracil