The transfection of thymidylate synthase antisense suppresses oncogenic properties of a human colon cancer cell line and augments the antitumor effect of fluorouracil

Matsuoka, Kinya; Tsukuda, Kazunori; Suda, Manabu; Kobayashi, Kazuya; Ota, Tetsuya; Okita, Atsushi; Watanabe, Keitaro; Suzuki, Eiji; Murakami, Masakazu; Doihara, Hiroyoshi; Shimizu, Nobuyoshi

doi:10.3892/ijo.24.1.217

Cited by 5 publications

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“…0.05). These results show that TS overexpression is frequent and that expression of this protein is linked to rapid tumor cell proliferation and poor prognosis in HNSCC patients, being consistent with the results of previous studies which found increased tumor cell proliferation in TS-positive breast and colon cancers [20,23] . In addition, our data revealed that overall survival was significantly longer in the TS-negative group than in the TS-positive group.…”

Section: Discussionsupporting

confidence: 81%

“…Saga et al [22] reported that TS-overexpressing cervical cancer cells have decreased sensitivity to 5-FU. Matsuoka et al [23] also showed that in human colon cancer cells TS expression and activity were effectively inhibited by TS antisense treatment and the effect of 5-FU on cancer cells can be augmented. The present result is in agreement with those earlier studies.…”

Section: Discussionmentioning

confidence: 99%

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Correlations between Thymidylate Synthase Expression and Chemosensitivity to 5-Fluorouracil, Cell Proliferation and Clinical Outcome in Head and Neck Squamous Cell Carcinoma

Yasumatsu

Nakashima

Uryu³

et al. 2008

Chemotherapy

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Background: 5-Fluorouracil (5-FU) is a widely used drug in head and neck squamous cell carcinoma (HNSCC). Thymidylate synthase (TS), which is the target enzyme of 5-FU, has been demonstrated to be a key regulatory enzyme. In this study, we examined whether TS expression is correlated with chemosensitivity to 5-FU, cell proliferation and clinical outcome in HNSCC. Methods: An antisense TS cDNA was constitutively expressed in the HNSCC cell line. The effects of TS expression on in vitro cell growth and 5-FU cytotoxicity were examined. We also evaluated the association between TS expression and cell proliferation in surgical specimens, and prognosis in HNSCC patients. Results: Antisense TS transfection increases the cytotoxicity of 5-FU and inhibits cell proliferation in HNSCC cellsin vitro. Immunohistochemical expression of TS may have prognostic value in patients with HNSCC. Conclusions: These results indicate that TS expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Correlations between Thymidylate Synthase Expression and Chemosensitivity to 5-Fluorouracil, Cell Proliferation and Clinical Outcome in Head and Neck Squamous Cell Carcinoma

Yasumatsu

Nakashima

Uryu³

et al. 2008

Chemotherapy

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“…86,119,120 Chemosensitivity to 5-FU was also increased after transfection of human colon cancer cells with antisense TS cDNA. 121 However, conflicting data have been observed in clinical studies evaluating the prognostic role of mRNA, protein and activity levels of TS in relation to tumour response and clinical outcome to 5-FU-based chemotherapy. An overview of relevant clinical studies is presented in Table 4.…”

Section: Impact Of Somatic Mutations and Gene Expression Levels: 5-fumentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…The subsequent phosphorylation of dTMP to dTTP provides a direct precursor for DNA synthesis. Several in vitro studies with tumor cell lines have implicated up-regulation of TS expression as a mechanism of resistance to 5-FU that develops after exposure to the drug [16][17][18][19]. Previous clinical studies have also shown that a low level of TS expression was associated with high sensitivity to 5-FU, to 5-FU plus cisplatin, or to 5-FU plus methotrexate in colorectal or gastric cancer [11].…”

Section: Discussionmentioning

confidence: 93%

Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer

et al. 2011

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The transfection of thymidylate synthase antisense suppresses oncogenic properties of a human colon cancer cell line and augments the antitumor effect of fluorouracil

Cited by 5 publications

References 0 publications

Correlations between Thymidylate Synthase Expression and Chemosensitivity to 5-Fluorouracil, Cell Proliferation and Clinical Outcome in Head and Neck Squamous Cell Carcinoma

Correlations between Thymidylate Synthase Expression and Chemosensitivity to 5-Fluorouracil, Cell Proliferation and Clinical Outcome in Head and Neck Squamous Cell Carcinoma

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer

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