ArticleBritish journal of pharmacology1999
Antisense down-regulation of thymidylate synthase to suppress growth and enhance cytotoxicity of 5-FUdR, 5-FU and Tomudex in HeLa cells.
Article in British journal of pharmacology, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 46 citations in OpenAlex.
- Thymidylate synthase gene amplification predicts pemetrexed resistance in patients with advanced non-small cell lung cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2016Trial
- An insight into thymidylate synthase inhibitor as anticancer agents: an explicative review.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Detection of a G-Quadruplex as a Regulatory Element inInternational journal of molecular sciences · 2020Article
- Article
- Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer.Disease markers · 2015Article
- IDO Downregulation Induces Sensitivity to Pemetrexed, Gemcitabine, FK866, and Methoxyamine in Human Cancer Cells.PloS one · 2015Article
- Impact of thymidylate synthase protein expression on efficacy of chemotherapy in advanced lung cancer patients.Molecular and clinical oncology · 2013Article
- Mechanistic evaluation of the signaling events regulating curcumin-mediated chemosensitization of breast cancer cells to 5-fluorouracil.Cell death & disease · 2013Article
- Short hairpin RNA suppression of thymidylate synthase produces DNA mismatches and results in excellent radiosensitization.International journal of radiation oncology, biology, physics · 2012Article
- Thymidylate synthase as a determinant of pemetrexed sensitivity in non-small cell lung cancer.British journal of cancer · 2011Article
- Identification of thymidylate synthase as a potential therapeutic target for lung cancer.British journal of cancer · 2010Article
- Antisense targeting of thymidylate synthase (TS) mRNA increases TS gene transcription and TS protein: effects on human tumor cell sensitivity to TS enzyme-inhibiting drugs.Gene expression · 2007Article
- A "combination oligonucleotide" antisense strategy to downregulate thymidylate synthase and decrease tumor cell growth and drug resistance.Cancer gene therapy · 2003Article
- Antisense-induced down-regulation of thymidylate synthase and enhanced cytotoxicity of 5-FUdR in 5-FUdR-resistant HeLa cells.British journal of pharmacology · 2001Article
- Effect of 2'-O-methyl antisense ORNs on expression of thymidylate synthase in human colon cancer RKO cells.Nucleic acids research · 2001Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
1. Thymidylate synthase (TS), the key enzyme in de novo synthesis of thymidine, is an important target for antitumour chemotherapy. It was hypothesized that antisense oligonucleotide down-regulation of TS mRNA would decrease TS levels and enhance the cytotoxicity of inhibitors of TS, including the pyrimidine analogues 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine (5-FUdR), and the folate analogue Tomudex (ICI D1694; N-(5-[N-(3, 4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino ]-2-theon yl-L-glutamic acid). 2. 2'-Methoxyethoxylated, phosphorothioated 20-mer oligodeoxynucleotides (ODNs), complementary to various sequences in TS mRNA, were synthesized, along with control oligomers consisting of the same, respective bases in randomized order, against which all the biological effects were compared. Following a 6-h transfection of HeLa cells using polycationic liposome at 3 microg ml(-1), ODN 83 (50 nM), complementary to a region in the 3'-untranslated region of the TS mRNA, decreased TS mRNA levels by approximately 70% within 24 h. ODN 83 also decreased TS enzyme activity, as measured by binding of TS to radiolabelled 5-fluorodeoxyuridine monophosphate. In addition to inhibiting proliferation by up to approximately 40%, ODN 83 enhanced the cytotoxicity of Tomudex or 5-FU, added 1 day following transfection, by 50 - 60%. ODN 83 also enhanced sensitivity to 5-FUdR by 70%, but did not affect the toxicity of cisplatin, chlorambucil, melphalan, doxorubicin, ionizing radiation, paclitaxel, or irinotecan. 3. These data indicate that antisense ODN down-regulation of TS can inhibit human tumour cell proliferation and enhance the efficacy of TS-targeted drugs.
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