Evaluation of sensitivity to 5-FU on the basis of thymidylate synthase (TS)/dihydropyrimidine dehydrogenase(DPD) activity and chromosomal analysis in micro tissue specimens of breast cancer

Ota, Daisuke; Kusama, Mikio; Kojima, Hiroshi; Nakayama, S.; Misaka, Takeharu; Tsuchida, Akihiko; Aoki, Tatsuya

doi:10.1007/bf02968043

Cited by 5 publications

(3 citation statements)

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“…FdUMP and the folate cofactor 5-10-methylene tetrahydrofolate bind to TS to form a covalently-bound ternary complex that inhibits TS [32] . The expression level of TS among tumors varies considerably, and cellular sensitivity to 5-FU is related to alterations in the TS level [33] . In our study, insulin/5-FU treatment increased the level of the TS ternary complex and decreased the free TS expression compared with 5-FU treatment in the Ls-174-t cells.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with insulin enhances anticancer functions of 5-fluorou-racil in human esophageal and colonic cancer cells

Zou

Xie

2007

Acta Pharmacologica Sinica

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Aim: To investigate the effects of insulin on enhancing 5-fluorouracil (5-FU) anticancer functions and its mechanisms in the human esophageal cancer cell line (Eca 109) and human colonic cancer cell line (Ls-174-t). Methods: The effect of insulin/5-FU combination treatment on the growth of Eca 109 and Ls-174-t cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. After insulin treatment or insulin/5-FU treatment, cell cycle distribution of both cell lines was analyzed by flow cytometry. Western blot assay was used to assess the expression of caspase-3 and thymidylate synthase (TS). Apoptosis was detected by flow cytometry, DNA fragmentation assay, and terminal transferase dUTP nick end labeling assay (TUNEL). Moreover, the changes of 5-FU uptake after insulin pretreatment were detected by HPLC assay and Western blot analysis. Results: We found that insulin enhanced the inhibitory effect of 5-FU on cell proliferation when Eca 109 cells and Ls-174-t cells were pretreated with insulin for the appropriate time. Insulin increased the cell number of the S phase and the uptake of 5-FU. Insulin/5-FU treatment enhanced apoptosis of tumor cells and upregulated the expression of cleaved caspase-3 compared with 5-FU treatment. Moreover, insulin/5-FU treatment induced the changes of free TS and the TS ternary complex level compared with 5-FU treatment in Eca 109 and Ls-174-t cells. Conclusion: These data suggest that insulin enhances anticancer functions of 5-FU when it is treated before 5-FU for the appropriate time in human esophageal and colonic cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Pretreatment with insulin enhances anticancer functions of 5-fluorou-racil in human esophageal and colonic cancer cells

Zou

Xie

2007

Acta Pharmacologica Sinica

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“…Thymidylate synthase (TS) is an important enzyme for DNA synthesis and the target for 5-FU. Previous clinical studies have demonstrated that TS expression level predicts the response to 5-FU-based chemotherapy [8][9][10]. Moreover, patients with node-positive breast cancer with high TS expression demonstrated the most significant benefit of adjuvant 5-FU-containing chemotherapy.…”

Section: Introductionmentioning

confidence: 94%

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer

et al. 2010

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The efficacy of 5-FU may be lower in pancreatic cancer tissue than in normal tissue because DPD activity is upregulated in pancreatic cancer tissue compared to normal pancreatic tissue. It is necessary to develop an effective 5-FU delivery system and/or 5-FU combined with an inhibitor for DPD that can be used when 5-FU must be administered to patients with pancreatic cancer. High DPD activity may be a prognostic factor in patients with pancreatic cancer.

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“…One complicating factor is that the mRNA and protein activity levels do not necessarily coincide. For example, analysis of biopsies from breast cancer specimens revealed no correlation between DPD mRNA and DPD activity in tumor tissue (r 5 0.139, P 5 0.4423) [Ota et al, 2004].…”

Section: à3mentioning

confidence: 99%

Genetic determinants for activated fluoropyrimidine chemotherapy

Gmeiner

2006

Drug Development Research

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Fluoropyrimidines (FPs) remain widely used for the treatment of diverse malignancies more than four decades following the initial report of 5-fluorouracil (5FU), the archetypal FP, as a novel compound with potential anti-neoplastic activity. Subsequent decades of research have enriched our understanding of the biochemical mechanisms that are important for FP activation as well as the genetic determinants that are predictive of the likely success, or failure, of FP chemotherapy for a particular individual. The concept that chemotherapy should be customized to complement the genetic profiles of cancer patients has become increasingly important as genotyping of tumor samples has become possible and as the number of available anticancer drugs has increased. Significant progress has been made in identifying the gene expression profiles for cancer patients who are likely to benefit from treatment with FPs. In this review, we will summarize the results of retrospective clinical studies correlating response to FP chemotherapy with the expression of specific genes, such as TS and DPD. We will also present a summary of FPs in current clinical use, including orally bioavailable FPs such as capecitabine, as well as FPs that are in pre-clinical development, such as FdUMP [10]. Refinement of a target population through pharmacogenetic analysis and development of novel FPs that evoke very high response rates in this target population will likely result in the use of FP regimens in the coming era when cancer becomes a largely manageable disease. Drug Dev.

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Evaluation of sensitivity to 5-FU on the basis of thymidylate synthase (TS)/dihydropyrimidine dehydrogenase(DPD) activity and chromosomal analysis in micro tissue specimens of breast cancer

Abstract: TS mRNA showed a positive correlation with TS activity, suggesting that this method of using small amounts of tissue can replace anti-cancer drug sensitivity tests.

Cited by 5 publications

References 20 publications

Pretreatment with insulin enhances anticancer functions of 5-fluorou-racil in human esophageal and colonic cancer cells

Pretreatment with insulin enhances anticancer functions of 5-fluorou-racil in human esophageal and colonic cancer cells

Clinical significance of dihydropyrimidine dehydrogenase and thymidylate synthase expression in patients with pancreatic cancer

Genetic determinants for activated fluoropyrimidine chemotherapy

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