Genome-wide mRNA and microRNA profiling of the NCI 60 cell-line screen and comparison of FdUMP[10] with fluorouracil, floxuridine, and topoisomerase 1 poisons.

Abstract

A profile of microRNA (miRNA) and mRNA expression patterns across the NCI-60 cell-line screen was analyzed to identify expression signatures that correlate with sensitivity to FdUMP[10], fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP[10] resembles FdU most closely and shows dissimilarities with 5FU. FdUMP[10] had the largest dynamic range of any of these drugs across the NCI-60 indicative of cancer cell-specific activity. Genes involved in endocytosis, such as clathrin (CLTC), SNF8, annexin A6 (ANXA6), and amyloid protein-binding 2 (APPBP2) uniquely correlated with sensitivity to FdUMP[10], consistent with a protein-mediated cellular uptake of FdUMP[10]. Genes involved in nucleotide metabolism were enriched for the three fluoropyrimidine drugs, with the expression profile for 5FU correlated to an RNA-mediated cytotoxic mechanism, whereas expression of glycosyltransferases (XYLT2) that use UDP sugars as substrates and the nucleoside diphosphatase and metastasis suppressor NM23 (NME1) were associated with FdUMP[10] sensitivity. Topotecan and irinotecan had significant negative correlations with miR-24, a miRNA with a high aggregate P(CT) score for topoisomerase 1 (Top1). Our results reveal significant new correlations between FdUMP[10] and Top1 poisons, as well as new information on the unique cytotoxic mechanism and genomic signature of FdUMP[10].

• Authors: William H Gmeiner, William C Reinhold, Yves Pommier
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 12 Pg. 3105-14 (Dec 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 21159603 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: ©2010 AACR.

Chemical References

• FdUMP(10)
• MicroRNAs
• Nucleosides
• RNA, Messenger
• Topoisomerase I Inhibitors
• Floxuridine
• Fluorodeoxyuridylate
• Irinotecan
• Topotecan
• Fluorouracil
• Camptothecin

Topics

• Camptothecin (analogs & derivatives, chemistry, pharmacology)
• Cell Line, Tumor
• DNA Damage (genetics)
• DNA Repair (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Endocytosis (drug effects, genetics)
• Floxuridine (chemistry, pharmacology)
• Fluorodeoxyuridylate (analogs & derivatives, chemistry, pharmacology)
• Fluorouracil (chemistry, pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Genome, Human (genetics)
• Humans
• Irinotecan
• MicroRNAs (genetics, metabolism)
• National Cancer Institute (U.S.)
• Nucleosides (metabolism)
• RNA, Messenger (genetics, metabolism)
• Topoisomerase I Inhibitors (chemistry, pharmacology)
• Topotecan (chemistry, pharmacology)
• United States