Genome-wide mRNA and microRNA profiling of the NCI 60 cell-line screen and comparison of FdUMP with fluorouracil, floxuridine, and topoisomerase 1 poisons.
Molecular Cancer Therapeutics 9(12):3105 (2010)
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, fluorouracil (5FU), floxuridine (FdU), topotecan, and irinotecan. Genome-wide profile analyses revealed FdUMP resembles FdU most closely and shows dissimilarities with 5FU. FdUMP 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, consistent with a protein-mediated cellular uptake of FdUMP. 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 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 and Top1 poisons, as well as new information on the unique cytotoxic mechanism and genomic signature of FdUMP.
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