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Cancer Biomarkers
Published in Trevor F. Cox, Medical Statistics for Cancer Studies, 2022
We look at a study of two predictive biomarkers for pancreatic cancer, dihydropyrimidine dehydrogenase (DPD) and human equilibrative nucleoside transporter-1 (hENT1)[19]. Tumour tissue samples had been taken, prior to treatment, from patients who received chemotherapy treatment by GEM or 5FU in the ESPAC3 trial and stored in freezers at very low temperature. Cores taken from these tissue samples were placed in tissue microarrays, from which sections were cut and placed on slides, there being between four and eight sections per patient. The sections were stained so that DPD could be measured and then each was scored on a 0–3 point system by two pathologists: 0 – no staining, 1 – weak, 2 – moderate, 3 – strong staining. The more staining there is, the higher the DPD expression in the tumour. A patient's final score was taken as the mean, to the nearest integer, over all their section scores. This was converted to low and high DPD expression status; low-scores were 0,1; high-scores were 2,3. The hENT1 scores had been found for the patients in a previous translational study, using staining and determining a cutpoint to assess hENT1 expression as low and high. We will carry out some statistical analyses similar to those that appear in the DPD/hENT1 publication.
Pancreatic Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Kulbir Mann, Andrea Sheel, Paula Ghaneh
With the advent of multiple chemotherapy regimens that improve survival, with the associated morbidities, there is an onus on tailoring specific therapies to the individual patient. An example is that low serum hENT1 (human equilibrative nucleoside transporter 1) has been associated with a poor response to gemcitabine monotherapy.153,154 A recent Cochrane review suggested that for advanced cancer, combination chemotherapy confers most benefit, and biomarker development is essential for personalized selection for patients.121 The Precision Panc project aims to molecularly profile all patients with pancreatic cancer, both resectable and advanced disease, in association with clinical trials with differing chemotherapy arms. The results of these studies will provide valuable information for the future of pancreatic cancer management.
Drugs of Abuse and Addiction
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Aarushi Singh
Alcohol is the most addictive drug used. Like nicotine, alcohol is also a part of second class of mechanistic classification of drugs (Morrow, 1995; Koob et al., 1998). No single receptor is involved in effect of alcohol. Alcohol alters quite a range of receptors like GABA receptors, nAChR, NMDA receptors, GIRK channels (Morrow, 1995; Koob et al., 1998; Luscher et al., 2006). Apart from these, adenosine re-uptake is also influenced by alcohol by obstructing the equilibrative nucleoside transporter (ENT1). Alcohol also increases dopamine release like all other drugs but the exact mechanism behind this is not known in the case of alcohol (Morrow, 1995; Koob et al., 1998). This increase can be due to direct excitation of DA neurons or may be due to any other altered receptor. Involvement of all the different receptors in the action pathway of alcohol make it unclear what is the actual reason of its addiction (Koob et al., 1998; Morrow, 1995).
Advancement in transporter-oriented nanoplatforms for cancer therapy
Published in Journal of Drug Targeting, 2023
Yunchun Zhao, Shuya Ye, Yao Zhu, Yue Chen, Shan Yang, Fengmei Wang, Rong Wang, Dongxu Qin, Dongli Sun, Caihong Zheng
One of the main characteristics of tumour tissue is rapid growth [151]. In addition to having a high capacity to absorb biotin and amino acids, cancer cells have a considerably higher requirement for nucleosides than normal cells. For nucleosides to cross cell membranes, specialised transporters are required. In the family of nucleoside transporters, ENT1 is the purine and pyrimidine transporter with the greatest expression and selectivity. According to a number of studies, ENT1 may work effectively as a target for possible cancer-related medications [152–155]. In a previous study, we discovered that ENT1 was overexpressed in choriocarcinoma cells (JEG-3 cells) by investigating transporter expression. In our previous study, we designed and synthesised cytarabine (Cy, a substrate of ENT1)-grafted liposomes (Cy-Lipo) for the targeted delivery of methotrexate (Cy-Lipo@MTX) to treat choriocarcinoma. High Cy-Lipo affinity is demonstrated by ENT1, which is also capable of mediating the endocytosis of synthetic nanocarriers into JEG-3 cells. During endocytosis, the ENT1 protein recycles and regenerates to maintain its transport function. Bio-distribution studies further showed that Cy-Lipo exhibited high accumulation and retention in tumours. Furthermore, the designed DSPE-PEG2K-Cy conjugate had a synergistic therapeutic effect on choriocarcinoma (Figure 6) [121]. This study revealed that ENT1 has significant potential as a highly effective target for the logical design of tailored nanotherapeutic treatments when overexpressed on choriocarcinoma cells.
Approaches for designing and discovering purinergic drugs for gastrointestinal diseases
Published in Expert Opinion on Drug Discovery, 2020
Diego Dal Ben, Luca Antonioli, Catia Lambertucci, Andrea Spinaci, Matteo Fornai, Vanessa D’Antongiovanni, Carolina Pellegrini, Corrado Blandizzi, Rosaria Volpini
In parallel, under physiological conditions, the levels of purines are finely tuned also by the activity of the nucleoside transporters [47]. Nowadays, these transporters are classified as: (a) equilibrative nucleoside transporters (ENTs), designated as ENT1, ENT2, ENT3, and ENT4, which transport nucleosides across cell membranes in either directions, based on concentration gradients; (b) concentrative nucleoside transporters (CNTs), classified in CNT1, CNT2, and CNT3, promoting the intracellular influx of nucleosides against their concentration gradient, using the sodium ion gradient across cellular membranes as a source of energy [48]. Once transported intracellularly, Ado gets phosphorylated to AMP by the intracellular adenosine kinase (ADK) enzyme, which controls the poly-phosphorylation of Ado to ATP. Intracellular Ado may also be converted to inosine by the intracellular ADA [39].
RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment
Published in Expert Opinion on Investigational Drugs, 2019
Beatrice Balboni, Btissame El Hassouni, Richard J. Honeywell, Dzjemma Sarkisjan, Elisa Giovannetti, Julie Poore, Callie Heaton, Christine Peterson, Ely Benaim, Young B. Lee, Deog J. Kim, Godefridus J. Peters
From the initial mechanism of action studies, several potential markers were identified in various model systems and characterized for their expression in human normal and tumor tissues. These potential biomarkers are either related to its metabolism or its identified targets. RX-3117 is transported into the cell by the hENT1. Since inhibition of hENT results in a decreased sensitivity and since a deficiency of hENT even in complete resistance, it can be postulated that at least a certain expression of hENT is required for cells to be sensitive to RX-3117. For gemcitabine, it has been demonstrated that sensitivity of PDAC is related to hENT1 expression, either measured by PCR [40] or by immunohistochemistry [41]. Patients with a higher ENT1 expression had a longer survival. Care has to be taken that a proper antibody is being used for immunostaining since the original antibody developed by Cass et al. clearly showed a relation with efficacy of gemcitabine [41] and patients with a higher expression had a longer survival. However, the antibody SP120 also stained positive in cells with a deficient hENT expression [42]; this antibody was used in a pivotal prospective study comparing gemcitabine and the prodrug CO1.01 (CP-4126) which can bypass the hENT transporter and shows sensitivity in transport inhibited cells [43]. In this clinical study, no difference in survival of gemcitabine-treated patients with low and high positive staining with SP120 was found [44] so that it was incorrectly concluded that hENT was not related to gemcitabine’s efficacy. Using another proper antibody, a relation was found for high and low expression of hENT, which was validated with PCR, and showed a large difference in hENT in xenografts and patient samples.