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T Kunicka, P Prochazka, I Krus, P Bendova, M Protivova, S Susova, V Hlavac, V Liska, P Novak, M Schneiderova, P Pitule, J Bruha, O Vycital, P Vodicka, P Soucek
BACKGROUND: This study addresses involvement of major 5-fluorouracil (5-FU) pathway genes in the prognosis of colorectal carcinoma patients. METHODS: Testing set and two validation sets comprising paired tumor and adjacent mucosa tissue samples from 151 patients were used for transcript profiling of 15 5-FU pathway genes by quantitative real-time PCR and DNA methylation profiling by high resolution melting analysis. Intratumoral molecular profiles were correlated with clinical data of patients...
October 12, 2016: BMC Cancer
Thomas Wanek, Katharina Kreis, Petra Križková, Anna Schweifer, Christoph Denk, Johann Stanek, Severin Mairinger, Thomas Filip, Michael Sauberer, Patricia Edelhofer, Alexander Traxl, Viktoria E Muchitsch, Kurt Mereiter, Friedrich Hammerschmidt, Carol E Cass, Vijaya L Damaraju, Oliver Langer, Claudia Kuntner
Positron emission tomography (PET) using fluorine-18 ((18)F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[(18)F]fluoro-β-d-allofuranosyl)-2-nitroimidazole (β-[(18)F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [(18)F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β-6) in a final radiochemical yield of 12±8% (n=10, based on [(18)F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/μmol (n=10)...
November 1, 2016: Bioorganic & Medicinal Chemistry
Xavier Guitart, Jordi Bonaventura, William Rea, Marco Orrú, Lucrezia Cellai, Ilaria Dettori, Felicita Pedata, Marc Brugarolas, Antonio Cortés, Vicent Casadó, Ching-Pang Chang, Manikandan Narayanan, Yijuang Chern, Sergi Ferré
The initial goal of this study was to investigate alterations in adenosine A2A receptor (A2AR) density or function in a rat model of Huntington disease (HD) with reported insensitivity to an A2AR antagonist. Unsuspected negative results led to the hypothesis of a low striatal adenosine tone and to the search for the mechanisms involved. Extracellular striatal concentrations of adenosine were measured with in vivo microdialysis in two rodent models of early neuropathological stages of HD disease, the Tg51 rat and the zQ175 knock-in mouse...
August 24, 2016: Neurobiology of Disease
Rhiannon McBean, Yew-Wah Liew, Brett Wilson, Pawinee Kupatawintu, Morakot Emthip, Catherine Hyland, Robert Flower
The At(a) blood group antigen (now AUG2 in the Augustine system) is a high-frequency antigen with negative phenotype At(a-) found only in individuals of African ancestry. In a twin pregnancy, the fifth pregnancy in a woman of African origin, serological investigations confirmed that the mother was At(a-) and anti-At(a) was detected. DNA samples were exome sequenced and alignment was performed to allow variant calling. It was confirmed that the single nucleotide polymorphism, rs45458701, within the SLC29A1 gene encoding the ENT1 protein, recently reported to be a basis of the At(a-) phenotype was also the basis of the phenotype in this family...
January 2016: Journal of Pathology. Clinical Research
Jeong-Hyun Kim, Chansu Lee, Hyun Sub Cheong, Youngil Koh, Kwang-Sung Ahn, Hyung-Lae Kim, Hyoung Doo Shin, Sung-Soo Yoon
PURPOSE: The solute carrier family 29 (equilibrative nucleoside transporter), member 1 (SLC29A1) is known to be involved in the transportation and resistance of the nucleoside analog cytosine arabinoside (AraC), one of the most effective drugs in the treatment of acute myeloid leukemia (AML). METHODS: In vitro functional analysis in AML cells and genetic association study were performed. RESULTS: Our functional analysis of SLC29A1 on anticancer effects of AraC showed that cytotoxic effects of AraC in AML cell lines were decreased by the reduction of SLC29A1 expression (P < 0...
September 2016: Cancer Chemotherapy and Pharmacology
Albert Català, Marçal Pastor-Anglada, Liska Caviedes-Cárdenas, Roberta Malatesta, Susana Rives, Nerea Vega-García, Mireia Camós, Paula Fernández-Calotti
FLT3 abnormalities are negative prognostic markers in acute leukemia. Infant leukemias are a subgroup with frequent MLL (KMT2A) rearrangements, FLT3 overexpression and high sensitivity to cytarabine, but dismal prognosis. Cytarabine is transported into cells by Human Equilibrative Nucleoside Transporter-1 (hENT1, SLC29A1), but the mechanisms that regulate hENT1 in acute leukemia have been scarcely studied.We explored the expression and functional link between FLT3 and main cytarabine transporters in 50 pediatric patients diagnosed with acute lymphoblastic leukemia and MLL rearrangement (ALL-MLL+) and other subtypes of leukemia, and in leukemia cell lines...
July 6, 2016: Oncotarget
Eric A Benson, Michael T Eadon, Zeruesenay Desta, Yunlong Liu, Hai Lin, Kimberly S Burgess, Matthew W Segar, Andrea Gaedigk, Todd C Skaar
UNLABELLED: Membrane drug transporters contribute to the disposition of many drugs. In human liver, drug transport is controlled by two main superfamilies of transporters, the solute carrier transporters (SLC) and the ATP Binding Cassette transporters (ABC). Altered expression of these transporters due to drug-drug interactions can contribute to differences in drug exposure and possibly effect. In this study, we determined the effect of rifampin on gene expression of hundreds of membrane transporters along with all clinically relevant drug transporters...
2016: Frontiers in Pharmacology
Farid Kheloufi, Eric Bellissant, Laurent Cotte, Isabelle Poizot-Martin, Sylvie Quaranta, Rodolphe Garraffo, Aurélie Barrail-Tran, Alain Renault, Isabelle Fournier, Bruno Lacarelle, Marc Bourlière, Jean-Michel Molina, Caroline Solas
OBJECTIVES: Ribavirin (RBV) induced anemia may be influenced by host genetic factors affecting RBV transport solute carrier (SLC) or metabolism inosine triphosphatase (ITPA), as already reported. We investigated the influence of single nucleotide polymorphisms (SNPs) on SLC genes on anemia, RBV trough concentration (Ctrough) and response in HIV-hepatitis C virus coinfected patients receiving triple therapy with boceprevir or telaprevir. METHODS: Patients from the ANRS HC26/HC27 studies were genotyped for SLC28A3 SNPs (rs10868138 and rs56350726) and SL29A1 SNPs (rs760370)...
August 24, 2016: AIDS
Hiroyuki Kitao, Yosuke Morodomi, Shinichiro Niimi, Mamoru Kiniwa, Kazuhiko Shigeno, Kazuaki Matsuoka, Yuki Kataoka, Makoto Iimori, Eriko Tokunaga, Hiroshi Saeki, Eiji Oki, Yoshihiko Maehara
Trifluridine (FTD) is a key component of the novel oral antitumor drug TAS-102 (also named TFTD), which consists of FTD and a thymidine phosphorylase inhibitor. FTD is supposed to exert its cytotoxicity via massive misincorporation into DNA, but the underlying mechanism of FTD incorporation into DNA and its correlation with cytotoxicity are not fully understood. The present study shows that several antibodies against 5-bromo-2'-deoxyuridine (BrdU) specifically cross-react with FTD, either anchored to bovine serum albumin or incorporated into DNA...
2016: Scientific Reports
Ragia H Ghoneim, Micheline Piquette-Miller
Altered expression of drug transporters and metabolic enzymes is known to occur in infection-induced inflammation. We hypothesize that in human immunodeficiency virus (HIV)-infected individuals, further alteration could occur as a result of augmented inflammation. The HIV-1 transgenic (Tg) rat is used to simulate HIV pathologies associated with the presence of HIV viral proteins. Therefore, the objective of this study was to examine the effect of endotoxin administration on the gene expression of drug transporters in the liver of HIV-Tg rats...
May 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Mi-Na Lee, Ben Kang, So Yoon Choi, Mi Jin Kim, Sook Young Woo, Jong-Won Kim, Yon Ho Choe, Soo-Youn Lee
BACKGROUND: Thiopurine-related toxicity results in discontinuation of therapy in up to 30% of patients with inflammatory bowel disease. Although thiopurine S-methyltransferase (TPMT) is implicated in toxicity, not all toxicity can be attributed to TPMT polymorphisms. We investigated the effects of polymorphisms of genes involved in thiopurine and folate metabolism pathways on 6-thioguanine nucleotide levels and toxicity. METHODS: Retrospective clinical data and blood samples were collected from 132 pediatric patients with inflammatory bowel disease treated with azathioprine...
December 2015: Inflammatory Bowel Diseases
Andrea Lombardi, Simona Landonio, Carlo Magni, Stefania Cheli, Cristina Mazzali, Mario U Mondelli, Giuliano Rizzardini, Emilio Clementi, Felicia Stefania Falvella
Chronic hepatitis C is one of the most important causes of liver disease, leading to cirrhosis, hepatic decompensation and hepatocellular carcinoma. Recently some important advances in therapy have been achieved with the introduction of first wave, first generation direct acting antiviral agents (DAAs) such as boceprevir (BOC), in combination with pegylated interferon (Peg-IFN) and ribavirin (RBV). The superior rate of sustained virological response with this treatment is accompanied by an elevated frequency of anaemia...
2015: Pharmacology
Mohammad Salem Hareedy, Ehab S El Desoky, Jean-Baptiste Woillard, Romany Helmy Thabet, Amany Mohamad Ali, Pierre Marquet, Nicolas Picard
AIM: We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. MATERIALS & METHODS: Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were investigated using a Cox proportional hazard model in 70 acute lymphoblastic leukemia patients from upper Egypt...
2015: Pharmacogenomics
Jessica Cusato, Sarah Allegra, Amedeo De Nicolò, Lucio Boglione, Giovanna Fatiguso, Giuseppe Cariti, Alessia Ciancio, Antonina Smedile, Silvia Strona, Giulia Troshina, Mario Rizzetto, Giovanni Di Perri, Antonio D'Avolio
In 2011 direct-acting antivirals, including telaprevir, have been developed to achieve a better antiviral effect. It was reported that telaprevir is a substrate of P-glycoprotein (ABCB1) and cytochrome P450 3A4. The aim of this retrospective study was the evaluation of the influence of some single nucleotide polymorphisms (SNPs) of genes (ABCB1, SLC28A2/3, SLC29A1) involved in TLV and RBV transport and their correlation with plasma TLV drug exposure at 1 month of therapy. We also investigated the association of a SNP in ABCB11 gene, whose role in TLV transport was not yet shown...
February 2015: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Sarah Allegra, Jessica Cusato, Amedeo De Nicolò, Lucio Boglione, Alberto Gatto, Giuseppe Cariti, Giovanni Di Perri, Antonio D'Avolio
Ribavirin is phosphorylated by adenosine kinase 1 (AK1) and cytosolic 5'-nucleotidase 2 and it is transported into cells by concentrative nucleoside transporters (CNT) 2/3, coded by SLC28A2/3 genes, and equilibrative nucleoside transporters (ENT) 1/2, coded by SLC29A1/2 genes. We evaluated the association of some polymorphisms of IL28B, SLC28A2/3, SLC29A1, ABCB1, NT5C2, AK1, HNF4α genes and ribavirin treatment outcome and pharmacokinetics after 4weeks of therapy, in a cohort of HCV-1/4 Italian patients. Allelic discrimination was performed by real-time PCR; plasma concentrations were determined at the end of dosing interval (Ctrough) using an HPLC-UV method...
February 2015: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Laura Milazzo, Anna Maria Peri, Cristina Mazzali, Carlo Magni, Elisa Calvi, Amedeo De Nicolò, Emilio Clementi, Stefania Cheli, Antonio D'Avolio, Spinello Antinori, Felicia Stefania Falvella
OBJECTIVES: The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the SLC29A1 gene, encoding ENT1, may influence ribavirin-associated anaemia, which is observed at a higher incidence with telaprevir in combination with pegylated-IFNα and ribavirin than with pegylated-IFNα and ribavirin alone. In this study, we investigated the role of the rs760370 SLC29A1 variant in ribavirin-induced anaemia in chronic hepatitis C patients treated with telaprevir-based triple therapy...
April 2015: Journal of Antimicrobial Chemotherapy
Krisztina Mita Gabor, Geza Schermann, Orsolya Lautner-Csorba, Ferenc Rarosi, Daniel J Erdelyi, Emoke Endreffy, Krisztina Berek, Katalin Bartyik, Csaba Bereczki, Csaba Szalai, Agnes F Semsei
BACKGROUND: Cytarabine (cytosine arabinoside, ara-C) is a chemotherapeutical agent used in the treatment of pediatric acute lymphoblastic leukemia (ALL). Adverse drug reactions, such as interpatient variability in sensitivity to ara-C, are considerable and may cause difficulties during chemotherapy. Single nucleotide polymorphisms (SNPs) can play a significant role in modifying nucleoside-drug pharmacokinetics and pharmacodynamics and thus the development of adverse effects. Our aim was to determine whether polymorphisms in genes encoding transporters and enzymes responsible for the metabolism of ara-C are associated with toxicity and clinical outcome in a patient population with childhood ALL...
April 2015: Pediatric Blood & Cancer
Haixia Wan, Jianyi Zhu, Fangyuan Chen, Fei Xiao, Honghui Huang, Xiaofeng Han, Lu Zhong, Hua Zhong, Lan Xu, Beiwen Ni, Jihua Zhong
BACKGROUND: The mechanism behind poor survival of acute myeloid leukemia (AML) patients with 1-barabinofuranosylcytosine (Ara-C) based treatment remains unclear. This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML. METHODS: The genotypes of 19 single nucleotide polymorphisms (SNPs) of DCK, CDA and SLC29A1from 100 AML patients treated with Ara-C were examined. All the SNPs were screened with ligase detection reaction assay...
2014: Journal of Experimental & Clinical Cancer Research: CR
Francisco Westermeier, Carlos Salomón, Marcelo Farías, Pablo Arroyo, Bárbara Fuenzalida, Tamara Sáez, Rocío Salsoso, Carlos Sanhueza, Enrique Guzmán-Gutiérrez, Fabián Pardo, Andrea Leiva, Luis Sobrevia
Reduced adenosine uptake via human equilibrative nucleoside transporter 1 (hENT1) in human umbilical vein endothelial cells (HUVECs) from gestational diabetes mellitus (GDM) is reversed by insulin by restoring hENT1 expression. Insulin receptors A (IR-A) and B (IR-B) are expressed in HUVECs, and GDM results in higher IR-A mRNA expression vs. cells from normal pregnancies. We studied whether the reversal of GDM effects on transport by insulin depends on restoration of IR-A expression. We specifically measured hENT1 expression [mRNA, protein abundance, SLC29A1 (for hENT1) promoter activity] and activity (adenosine transport kinetics) and the role of IR-A/IR-B expression and signaling [total and phosphorylated 42 and 44 kDa mitogen-activated protein kinases (p44/42(mapk)) and Akt] in IR-A, IR-B, and IR-A/B knockdown HUVECs from normal (n = 33) or GDM (n = 33) pregnancies...
January 2015: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Tuvshinjargal Gotovdorj, Eunil Lee, Yongchul Lim, Eun Jeong Cha, Daeho Kwon, Eunyoung Hong, YunJeong Kim, Min-Yeong Oh
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin...
September 2014: Journal of Korean Medical Science
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