High hENT1 Expression Research Articles

Expression levels of nucleoside transporter hENT1 and dCK enzyme, as prognostic factors in patients with AML treated with cytarabine.

6599 Background: Cytarabine has been set as the main drug included in different schemas for the treatment of AML patients. This drug requires inflow to the cell by the nucleoside transporter hENT1 and its activation rate is limited by dCK enzyme. Therefore decreased expression levels of these genes may influence response rate to this drug. Methods: AML patients > 15 years, without previous treatment were included. After informed consent signature, peripheral blood was obtained and DNA was extracted by standard methodology. Amplification of hENT1 and dCK genes was done by RT-PCR. Clinical parameters were registered. All patients received cytarabine + doxorrubicine as induction regimen (7 + 3 schema). Descriptive statistics was used. Uni- and multivariate analysis was done to determine factors influencing on response and overall survival. This protocol was approved by local IRB. Results: From January till December 2011, 22 patients have been included. Median age was 36 years (15-72 y), 52.3 % were male. According with FAB classification, M2 subtype was the most frequent (28.5 %). All patients had an adequate performance status (ECOG 1 & 2 = 34 & 66 %, respectively). Cytogenetic risk was considered as intermediate risk in 38 %, followed by unfavorable in 28 %. Complete response was achieved in 58 %. Higher hENT1 expression levels was the only factor influencing on response and survival by Spearmen correlation analysis. Conclusions: These are preliminary results but are highly suggestive that pharmacogenetic analysis regarding cytarabine inflow may be decisive in AML patients. Our results require to be confirmed with a larger sample, and a longer follow-up.

An analysis of human equilibrative nucleoside transporter‐1, ribonucleoside reductase subunit M1, ribonucleoside reductase subunit M2, and excision repair cross‐complementing gene‐1 expression in patients with resected pancreas adenocarcinoma

AbstractBACKGROUND:Tumor overexpression of excision repair cross‐complementing gene‐1 (ERCC1) may be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Human equilibrative nucleoside transporter‐1 (hENT1) and ribonucleoside reductase subunits M1 and M2 (RRM1 and RRM2) are integral to cellular transport and DNA synthesis and are implicated as poor prognostic factors in other malignancies. To the authors's knowledge, their role in PAC is not defined.METHODS:A prospective database was used to randomly select 95 patients who underwent pancreaticoduodenectomy for PAC between January 2000 and October 2008. Immunohistochemical analysis was performed on tumor samples for hENT1, RRM1 and RRM2, and ERCC1. Main outcomes were recurrence‐free survival (RFS) and overall survival (OS).RESULTS:The median follow‐up, RFS, and OS were 49 months, 10.6 months, and 15.5 months, respectively. The median tumor size was 3 cm. Approximately 26% of patients had positive microscopic margins, 61% had lymph node involvement, and 88% and 45% had perineural and lymphovascular invasion, respectively. High tumor expression of hENT1, RRM1, RRM2, and ERCC1 was present in 85%, 40%, 17%, and 16%, respectively, of patients. High hENT1 expression was associated with reduced RFS (9.5 months vs 44.5 months; P = .029), but not with OS. RRM1 expression was not associated with survival. High RRM2 expression was associated with reduced RFS (6.9 months vs 16.0 months; P < .0001) and decreased OS (9.1 months vs 18.4 months; P < .0001). High ERCC1 expression was associated with reduced RFS (6.1 months vs 15 months; P = .04) and decreased OS (8.9 months vs 18.1 months; P = .03). After accounting for known adverse tumor factors, high expression of RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS. A subset analysis of patients who received adjuvant therapy (n = 74) revealed the same negative effect of high RRM2 and ERCC1 expression on RFS and OS.CONCLUSIONS:High tumor expression of RRM2 and ERCC1 are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help to personalize adjuvant therapy. Cancer 2013. © 2012 American Cancer Society.

1893 THE SIGNIFICANCE OF COMBINED ANALYSIS OF HUMAN EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 (HENT1) AND RIBONUCLEOTIDE REDUCTASE M1 (RRM1) IN ADVANCED BLADDER CANCER PATIENTS WITH GEMCITABINE-BASED CHEMOTHERAPY

You have accessJournal of UrologyBladder Cancer: Metastatic Disease/Staging1 Apr 20121893 THE SIGNIFICANCE OF COMBINED ANALYSIS OF HUMAN EQUILIBRATIVE NUCLEOSIDE TRANSPORTER 1 (HENT1) AND RIBONUCLEOTIDE REDUCTASE M1 (RRM1) IN ADVANCED BLADDER CANCER PATIENTS WITH GEMCITABINE-BASED CHEMOTHERAPY Nagahide Matsumura, Hiroki Kusumoto, Yumiko Sasaki, Satoshi Nishizawa, Kuniyoshi Ura, Kazuro Kikkawa, Yoshiki Kodama, Motohiro Koh, Yasushi Nakamura, Yasuo Kohjimoto, and Isao Hara Nagahide MatsumuraNagahide Matsumura Wakayama City, Japan More articles by this author , Hiroki KusumotoHiroki Kusumoto Wakayama City, Japan More articles by this author , Yumiko SasakiYumiko Sasaki Wakayama City, Japan More articles by this author , Satoshi NishizawaSatoshi Nishizawa Wakayama City, Japan More articles by this author , Kuniyoshi UraKuniyoshi Ura Wakayama City, Japan More articles by this author , Kazuro KikkawaKazuro Kikkawa Wakayama City, Japan More articles by this author , Yoshiki KodamaYoshiki Kodama Wakayama City, Japan More articles by this author , Motohiro KohMotohiro Koh Wakayama City, Japan More articles by this author , Yasushi NakamuraYasushi Nakamura Wakayama City, Japan More articles by this author , Yasuo KohjimotoYasuo Kohjimoto Wakayama City, Japan More articles by this author , and Isao HaraIsao Hara Wakayama City, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.2049AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Human Equilibrative Nucleoside Transporter 1 (hENT1) and Ribonucleotide reductase M1 (RRM1) play important roles in pharmacokinetics of Gemcitabine, and Excision repair cross-complementing 1(ERCC1)is related to drug resistance to CDDP. We evaluated the expression level of these molecules in patients with metastatic bladder cancer treated with Gemcitabine-Cisplatin (GC)-based chemotherapy. METHODS Clinical data were retrieved from the databases from May 2002 to October 2011 in 40 patients (age35-88; male 36 female 4) with advanced bladder cancer treated by GC (Gemcitabine+Cisplatin) regimen (17 pts) and GCT (GC+Paclitaxel) regimen (23 pts). Inclusion criteria for this study were clinically and/or histologically documented advanced and/or metastatic (stage 4) bladder cancer. We performed immunohistochemical staining chemo-naive primary bladder tumor specimens with specific hENT1, RRM1 and ERCC1 antibodies. Pathologists blinded to clinical outcomes evaluated the expression level of these molecules. The clinical and histopathological data were analyzed to evaluate predictive factors. RESULTS With regards to anti tumor response, high hENT1 expression group showed better clinical response comparing with low hENT1 expression group (90% vs 35%, P<0.001). High hENT1 expression group and low RRM1 expression group showed significantly better survival (P<0.001, P=0.01 respectively, Kaplan-Meier curve Fig). Moreover, we classified the cohort patients into 3 subgroups based on the expression level of hENT1 and RRM1. The median survival time in group A was 19.3 months, which was significantly longer than that in Group C (9.9 months). Group B showed the intermediate survival curve between Group A and C (P<0.001, Kaplan-Meier curve, Fig). CONCLUSIONS The expression of hENT1 and RRM1 was associated with prolonged survival in patients with metastatic bladder cancer treated with GC-based chemotherapy. The combined analysis of hENT1 and RRM1 expression can be a promising biomarker which can predict the clinical response and the prognosis of patients with advanced bladder cancer treated by gemcitabine-based chemotherapy. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e763-e764 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nagahide Matsumura Wakayama City, Japan More articles by this author Hiroki Kusumoto Wakayama City, Japan More articles by this author Yumiko Sasaki Wakayama City, Japan More articles by this author Satoshi Nishizawa Wakayama City, Japan More articles by this author Kuniyoshi Ura Wakayama City, Japan More articles by this author Kazuro Kikkawa Wakayama City, Japan More articles by this author Yoshiki Kodama Wakayama City, Japan More articles by this author Motohiro Koh Wakayama City, Japan More articles by this author Yasushi Nakamura Wakayama City, Japan More articles by this author Yasuo Kohjimoto Wakayama City, Japan More articles by this author Isao Hara Wakayama City, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

An analysis of ERCC1, hENT1, RRM1, and RRM2 expression in resected pancreas adenocarcinoma: Implications for adjuvant treatment.

206 Background: Tumor overexpression of excision repair cross complementing gene 1 (ERCC1) was recently shown to be associated with decreased survival in patients with pancreas adenocarcinoma (PAC). Ribonucleotide reductase 1 and 2 (RRM) and human equilibrative nucleotide transporter 1 (hENT1) are integral to DNA synthesis and cellular transport and are implicated as poor prognostic factors in other malignancies. Their role in PAC is not well defined. Methods: A prospective database (n=220) was used to randomly select 95 pts who underwent pancreaticoduodenectomy for PAC between 1/00-10/08. IHC analysis was performed on tumor samples for RRM1 and 2, hENT1, and ERCC1. Main outcomes were recurrence-free (RFS) and overall survival (OS). Results: Median age was 63 yrs; median FU, RFS, and OS was 49, 10.6 and 15.5 mo. Median tumor size was 3cm, 26% had a positive margin, 34% were poorly differentiated, 61% had positive lymph nodes (LN), 88% had perineural invasion (PNI), and 45% had lymphovascular invasion (LVI). High expression of RRM1, RRM2, hENT1, and ERCC1 was present in 40%, 17%, 85%, and 16% of patients, respectively. High RRM2 was associated with reduced RFS (6.9 vs 16.0 mo; p&lt;0.0001) and decreased OS (9.1 vs 18.4 mo; p&lt;0.0001). High ERCC1 was associated with reduced RFS (6.1 vs 15 mo; p=0.04) and decreased OS (8.9 vs 18.1 mo; p=0.03). RRM1 and hENT1 were not associated with survival. After accounting for known adverse factors, high RRM2 and ERCC1 persisted as negative prognostic factors for RFS and OS (Table). A subset analysis of those who received adjuvant therapy (n=74) revealed the same negative effect of high RRM2 and ERCC1 on RFS and OS. Conclusions: High RRM2 and ERCC1 tumor expression are associated with reduced RFS and OS after resection of pancreas cancer. These biomarkers may help personalize adjuvant therapy. [Table: see text]

Immunohistochemical Analysis of Human Equilibrative Nucleoside Transporter-1 (hENT1) Predicts Survival in Resected Pancreatic Cancer Patients Treated with Adjuvant Gemcitabine Monotherapy

Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic cancer. Human equilibrative nucleoside transporter-1 (hENT1) is the major transporter responsible for gemcitabine uptake into cells. The aim of this study was to retrospectively determine the relationship between the outcome of pancreatic cancer after surgery followed by postoperative gemcitabine monotherapy and the expression of hENT1. A total of 27 resected pancreatic cancer patients treated with adjuvant gemcitabine were analyzed for tumor hENT1 expression via an immunohistochemical analysis. The staining intensity and the percentage of positive tumor cells were scored, and the composite score (hENT1 score) was obtained by obtaining the sum of these two scores. There were 11 patients assigned to the low hENT1 expression group, and 16 patients to the high hENT1 group. The patients with tumors that had higher hENT1 expression had a significantly longer disease-free survival (DFS) (log rank, P = 0.022) and overall survival (OS) (P = 0.024). The hENT1 expression was indicated to be a significant and independent prognostic factor for OS by the univariate (P = 0.030) and multivariate analyses (P = 0.019). A high expression of hENT1 in pancreatic cancer was found to be significantly associated with a longer survival in patients who received adjuvant gemcitabine monotherapy after curative resection, and hENT1 immunohistochemistry may well serve as a significant prognostic factor for these patients.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

The prognostic significance of human equilibrative nucleoside transporter 1 expression in patients with metastatic bladder cancer treated with gemcitabine‐cisplatin‐based combination chemotherapy

To evaluate the expression of the human equilibrative nucleoside transporter 1 (hENT1) and excision repair cross complementing 1 (ERCC1) as possible prognostic factors for patients with metastatic bladder cancer treated with gemcitabine-cisplatin-based combination chemotherapy. The present study retrospectively evaluated the expression of hENT1 and ERCC1 by immunostaining in chemo-naive primary bladder tumour specimens from 40 patients with metastatic bladder cancer who received treatment with gemcitabine-cisplatin-based combination chemotherapy at Wakayama Medical University Hospital and affiliated hospitals from May 2002 to July 2009. Immunohistochemistry on formalin-fixed, paraffin-embedded tissues was performed with specific hENT1 and ERCC1 antibodies scored by two pathologists who were blinded to clinical outcomes. The clinical and histopathological variables were analyzed to evaluate predictive values for survival. The median survival time in patients with high and low hENT1 expression was 17.3 and 11.6 months, respectively (log-rank test, P = 0.003). This contrasted with the median survival in patients with high and low ERCC1 expressions, which did not differ significantly (high ERCC1, 13.6 months; low ERCC1, 17.1 months; P = 0.178). In univariate Cox regression analyses for pretreatment clinicopathological variables, performance status (P = 0.02) and hENT1 expression (P = 0.004), but not ERCC1 expression (P = 0.182), were associated with overall survival. Multivariate analysis using a Cox proportional hazards model showed that hENT1 expression was an independent prognostic factor (P = 0.008). The data obtained in the present study show that high expression of hENT1 in tumour cells is associated with prolonged survival in patients with metastatic bladder cancer treated with gemcitabine-cisplatin-based combination chemotherapy.

KRAS, BRAF mutations, and HER2 expression in patients operated for pancreatic adenocarcinomas.

4043 Background: The results of cytostatic treatment in pancreatic ductal adenocarcinomas (PDAC) are still disappointing. Standard treatment is still gemcitabine, monotherapy or in combinations. Studies have shown an association between high hENT1 expression and response to Gemcitabine. New biological treatments have been tried with disappointing results. Activation of the KRAS oncogene is a key genetic step in the development and growth of PDAC. Most of these mutations occur in codon 12. Concomitant mutations in codons 13 and 61 are described. In colo-rectal cancer KRAS (codon 12,13) and BRAF (exon15, V600E) mutational status predict the response to treatment with monoclonal antibodies directed against the EGFR. In breast and gastric adenocarcinomas patients with HER3+ and 2+/FISH+ tumors benefits from Trastuzumab treatment. Aim:To describe the frequency of KRAS and BRAF mutations and the expression of HER2 in a population of patients operated for pancreatic (PDAC) and ampullary (AMPC) adenocarcinomas. Methods: Tumor specimens from 277 patients operated at Herlev Hospital were screened for KRAS and BRAF mutations using PCR and LightScanner (Idaho Technology). Samples suspected for mutations were selected for gene sequencing. DNA from KRAS wildtype (WT) samples was analysed again using TheraScreen KRAS mutation kit (DXS diagnostics). HER2 expression was analyzed by IHC, DAKO Hercep Test. Results: In PDAC 20% were WT and 72% had mutations in codon 12 and 13, 8% had other mutations. In AMPC 33% were WT and 55% had mutations in codon 12 and 13, 12% other mutations. Multivariate analysis showed that KRAS mutation was associated with short overall survival (OS) (HR = 1.48, 95% CI: 1.07-2.05, p = 0.02). Patients with codon 12 Asp or Val mutations had a shorter OS compared to WT and other KRAS mutations (HR = 1.79, 1.35-2.37, p = 0.0001). 22% of PDAC and 40% of ampullary cancers were both KRAS (codon12,13) and BRAF (exon15) WT. 7% PDAC and 13% AMPC were HER2 3+/2+. No association between BRAF or HER2 status and OS was found. Conclusions: We suggest that future studies should evaluate the effect of targeting EGFR in the subgroups of patients with PDAC or ampullary cancer with KRAS (codon 12,13) BRAF WT and HER2 in the HER2 3+, 2+/FISH+ subgroups. No significant financial relationships to disclose.

Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma

Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic adenocarcinoma and its use in combination with radiotherapy is under exploration. Human equilibrative nucleoside transporter 1 (hENT1) and human concentrative nucleoside transporter (hCNT) 1 and 3 are the major transporters responsible for 2',2'-difluoro-2-deoxycytidine (gemcitabine) uptake into cells. The aim of this study was to determine patients' outcome according to the expression of hENT1 and hCNT3 in tumoral cells after postoperative gemcitabine-based chemoradiation regimen. We studied tumor blocks from 45 pancreatic adenocarcinoma patients treated with gemcitabine-based chemoradiation after curative resection and assessed hENT1 and hCNT3 expression using immunohistochemistry. When adjusted for the effects of lymph node ratio and tumor diameter, patients with high hENT1 expression had significantly longer disease-free survival and overall survival (OS) than patients with low expression, whereas high hCNT3 expression was only associated with longer OS. In a combined analysis, patients with two favorable prognostic factors (hENT1(high)/hCNT3(high) expression) had a longer survival (median OS, 94.8 months) than those having one (median OS, 18.7 months) or no (median OS, 12.2 months) favorable prognostic factor. Pancreatic adenocarcinoma patients with a high expression of hENT1 and hCNT3 immunostaining have a significantly longer survival after adjuvant gemcitabine-based chemoradiation. These biomarkers deserve prospective evaluation in patients receiving gemcitabine-based adjuvant therapy.

High expression of nucleoside transporter hENT1 predicts a worse event-free survival in relapsed/refractory Hodgkin lymphoma patients treated with gemcitabine, vinorelbine, and liposomal doxorubicin—A CALGB 59804 correlative study

7581 Background: CALGB 59804 was a phase I/II trial of gemcitabine, vinorelbine, and liposomal doxorubicin (GVD) for pts with relapsed Hodgkin lymphoma (HL). Overall response rate (RR) was 70% (manuscript in review). Plasma membrane nucleoside transporters such as hENT1 are important in transporting nucleoside analogs into cells to exert their pharmacologic effects. We hypothesized high hENT1 expression would predict better RR and outcome in pts treated with GVD. Methods: 58 of 91 pts enrolled in CALGB 59804 had sufficient tissue for study; 31 relapse biopsies and 27 initial diagnosis biopsies. Expression of hENT1 was evaluated by immunohistochemistry in formalin fixed tissue and scored independently by two hematopathologists (RL and EH) blinded to the clinical outcomes. Positivity for hENT1 was defined as &gt;25% of Reed-Sternberg (RS) cells expressing hENT1. Expression was correlated with clinical factors, including IPS at relapse, as well as the overall (OS) and event-free survival (EFS). Results: Expression of hENT1 in RS cells was heterogeneous among cases. 28/58 cases (48%) were hENT1-positive. hENT1-expression was not associated with age, gender, stage, IPS (≤2 or &gt;2), or maximum toxicity grade (≤2 or &gt;2). Compared to hENT1-negative pts, hENT1-positive pts were less likely to have complete or partial response (19/30, 63% versus 22/28, 76%, P=0.20, chi square). hENT1 expression was not significantly associated with OS (P=0.18). Univariate log-rank analysis showed hENT1 positivity and IPS &gt;2 correlated significantly with a lower EFS (P=0.05, and P=0.03, respectively). Multivariate Cox regression analysis confirmed that IPS &gt;2 and hENT1 positivity were independent predictors of EFS (Hazard ratio 2.16, 95%CI 1.08–4.35, P=0.03; and Hazard ratio 2.10, 95% CI 1.06–4.19, P=0.03, respectively). P-values are two-sided. Conclusions: Contrary to our hypothesis, there is an inverse relationship between EFS and hENT1 expression in relapsed HL pts treated with GVD. High expression of hENT1 did not identify gemcitabine-sensitive disease, but may identify a biologically aggressive and/or treatment refractory subtype of HL. No significant financial relationships to disclose.