Small Interfering Double-Stranded RNAs as Therapeutic Molecules to Restore Chemosensitivity to Thymidylate Synthase Inhibitor Compounds

DOI PDF 被引用文献5件
  • John C. Schmitz
    Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine and VACT Cancer Center, VACT Healthcare System, West Haven, Connecticut
  • Tian-min Chen
    Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine and VACT Cancer Center, VACT Healthcare System, West Haven, Connecticut
  • Edward Chu
    Department of Medicine and Pharmacology, Yale Cancer Center, Yale University School of Medicine and VACT Cancer Center, VACT Healthcare System, West Haven, Connecticut

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<jats:title>Abstract</jats:title> <jats:p>RNA interference is a post-transcriptional mechanism by which double-stranded RNA specifically silence expression of a corresponding gene. Small interfering double-stranded RNA (siRNA) of 21–23 nucleotides can induce the process of RNA interference. Studies from our laboratory have shown that translation of thymidylate synthase (TS) mRNA is controlled by its own protein end-product TS in a negative autoregulatory manner. Disruption of this process gives rise to increased synthesis of TS and leads to the development of cellular drug resistance to TS-targeted compounds. As a strategy to inhibit TS expression at the mRNA level, siRNAs were designed to target nucleotides 1058–1077 on human TS mRNA. Transfection of TS1058 siRNA into human colon cancer RKO cells resulted in a dose-dependent inhibition of TS expression with an IC50 value of 10 pm but had no effect on the expression of α-tubulin or topoisomerase I. Inhibition of TS expression by TS1058 was maximal at 48 h and remained suppressed for up to 5 days. Pretreatment of RKO cells with TS1058 siRNA suppressed TS protein induction following exposure to raltitrexed. In addition, TS1058 restored chemosensitivity of the resistant RKO-HTStet cell line to various TS inhibitor compounds. On treatment with TS1058, IC50 values for raltitrexed, 1843U89, and 5-fluoro-2′-deoxyuridine decreased by ∼15–16-fold. These studies suggest that TS-targeted siRNAs are effective inhibitors of TS expression and may have therapeutic potential by themselves or as chemosensitizers in combination with TS inhibitor compounds.</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 64 (4), 1431-1435, 2004-02-15

    American Association for Cancer Research (AACR)

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