title: 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.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. bgmeiner@wfubmc.edu
authors.forename: William H
authors.initials: WH
authors.lastname: Gmeiner
authors.forename: William C
authors.initials: WC
authors.lastname: Reinhold
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D005467:Floxuridine / Q000737:chemistry / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005472:Fluorouracil / Q000737:chemistry / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D054547:National Cancer Institute (U.S.); D009705:Nucleosides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D019772:Topotecan / Q000737:chemistry / Q000494:pharmacology; D014481:United States
chemical_list: C435305:FdUMP(10); D035683:MicroRNAs; D009705:Nucleosides; D012333:RNA, Messenger; D059004:Topoisomerase I Inhibitors; D005467:Floxuridine; D005468:Fluorodeoxyuridylate; D000077146:Irinotecan; D019772:Topotecan; D005472:Fluorouracil; D002166:Camptothecin