Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer

Pérez-Torras, Sandra; García-Manteiga, José Manuel; Mercadé, Montse; Casado, F. Javier; Carbó, Neus; Pastor‐Anglada, Marçal; Mazo, Adela

doi:10.1016/j.bcp.2008.05.011

Cited by 41 publications

(31 citation statements)

References 27 publications

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“…In support of this concept, different molecular markers have been proposed to predict tumor response for the different drugs. TS, dihydropyrimidine dehydrogenase (DPD), 23 and mismatch repair enzymes are examples of putative predictive markers with 5-FU treatment 20 ; hENT1, 12,24,25 ribonucleotide reductase M1 (RRM1), 26 excision repair cross complementation group 1 (ERCC1), 26 dCK, 15 and HuR 16,17 are examples for gemcitabine. Clearly, the discovery and application of reliable predictive biomarkers to exploit non-overlapping pharmacogenomic profiles between the two principal backbone agents to treat PDA represents perhaps the "lowest-hanging fruit" in the effort to improve outcomes of this devastating disease, yet such biomarkers remain elusive.…”

Section: Introductionmentioning

confidence: 99%

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer

McAllister

Pineda

Jimbo

et al. 2014

Cancer Biology & Therapy

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Section: Introductionmentioning

confidence: 99%

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer

McAllister

Pineda

Jimbo

et al. 2014

Cancer Biology & Therapy

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“…Thus, we proposed that patients with the rs693955 CC genotype have lower expression levels of hENT1 and consequently, shorter TTR and lower hematological toxicity. In addition, Pérez-Torras et al [27] reported that overexpression of hENT1 in a relatively low transporter activity background increased the uridine uptake, resulting in a decreased amount of mRNA encoding key nucleotide metabolism enzymes, such as DCK and RR, and reduced cell cycle progression in the cell lines derived from human pancreatic adenocarcinomas. Nucleotide metabolism with the rs693955 CC genotype might be easy to change by the similar action of hENT1 overexpression.…”

Section: Discussionmentioning

confidence: 97%

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

et al. 2015

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Cytarabine arabinoside (Ara-C) is the most important agent for treating acute myeloid leukemia (AML). Here, we genotyped 11 single nucleotide polymorphisms (SNPs) of seven Ara-C metabolism-related genes in 39 AML patients who had received high-dose Ara-C as a single-agent treatment. Univariate analysis identified three SNPs that were significantly associated with shorter time-to-relapse (TTR): CTPS rs12144160 GG compared to AA/AG, DCTD rs9990999 AG/GG compared to AA, and SLC29A1 rs693955 CC compared to AA/AC. Multivariate analysis of TTR revealed the SLC29A1 rs693955 CC genotype and first induction failure to be significantly associated with a shorter TTR. The DCTD rs9990999 AG/GG and SLC29A1 rs693955 CC genotypes were also significantly associated with shorter duration of neutropenia. The results of our study suggest that SNP analysis can be an important tool in improving drug responsiveness and enabling a better understanding of this condition and the development of tailor-made treatments for AML patients who benefit from consolidated high-dose Ara-C therapy.

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“…However, clinical reports indicate limited effects in treated patients. Alterations in the uptake, or impairment at several enzymes in the metabolic pathway of gemcitabine such as equilibrative transports, cytidine deaminase, or deoxycytidine kinase have been reported as causes for this incomplete response in preclinical models and clinical samples (22)(23)(24). Another important contributing factor might arise from a poor distribution of gemcitabine in the tumor mass that will limit gemcitabine activity in areas close to tumor vessels or in the peritoneal surfaces when administered intraperitoneally (25).…”

Section: Discussionmentioning

confidence: 99%

Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect

Garcia-Rodríguez

Pérez-Torras

Carrió

et al. 2011

Molecular Cancer Therapeutics

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Gemcitabine is a nucleoside analogue with anticancer activity. Inside the cell, it is sequentially phosphorylated to generate the active drug. Phosphorylated nucleoside analogues have been shown to traffic through gap junctions. We investigated the participation of gap junctional intercellular communication (GJIC) as a possible mechanism spreading gemcitabine cytotoxicity in pancreatic tumors. Immunohistochemical analysis of pancreatic cancer biopsies revealed increased connexin 26 (Cx26) content but loss of connexins 32 (Cx32) and 43 (Cx43) expression. Cx26 abundance in neoplastic areas was confirmed by Cx26 mRNA in situ hybridization. Heterogeneity on the expression levels and the localization of Cx26, Cx32, and Cx43 were identified in pancreatic cancer cells and found to be associated with the extent of GJIC, and correlated with gemcitabine bystander cytotoxic effect. The abundance of Cx26 at the contact points in tumoral regions prompted us to study the involvement of Cx26 in the GJIC of gemcitabine toxic metabolites and their influence on the antitumoral effects of gemcitabine. Knockdown of Cx26 led to decreased GJIC and reduced gemcitabine bystander killing whereas overexpression of Cx26 triggered increased GJIC and enhanced the gemcitabine cytotoxic bystander effect. Gemcitabine treatment of mice bearing tumors, with a high GJIC capacity, resulted in a significant delay in tumor progression. Interestingly, gemcitabine administration in mice bearing tumors that overexpress Cx26 triggered a dramatic tumor regression of 50% from the initial volume. This study shows that Cx26 participates in the gap junction-mediated bystander cytoxic effect of gemcitabine and provides evidence that upregulation of Cx26 improves gemcitabine anticancer efficacy. Mol Cancer Ther; 10(3); 505-17. Ó2011 AACR.

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Adenoviral-mediated overexpression of human equilibrative nucleoside transporter 1 (hENT1) enhances gemcitabine response in human pancreatic cancer

Cited by 41 publications

References 27 publications

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer

Single nucleotide polymorphisms of cytarabine metabolic genes influence clinical outcome in acute myeloid leukemia patients receiving high-dose cytarabine therapy

Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect

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