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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.
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).
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
This chemotherapeutic agent is one of the most widely used pyrimidine analogues, with a very well established role in first-line treatment of advanced NSCLC. Several studies have examined molecular determinants of sensitivity to gemcitabine. Potential candidates to predict response include genes encoding drug metabolism enzymes, transport across membranes, or target proteins. One example is human equilibrative nucleoside transporter 1 (hENT1), which transports gemcitabine into cells. hENT1 basal expression levels have been correlated with IC50 values for gemcitabine in several NSCLC cell lines.25 Also, expression of hENT1 has been analyzed by IHC, suggesting that absence of hENT1 expression may be used to predict response to gemcitabine-based chemotherapy.26 Nevertheless, prospective studies are still required to validate this and the most accurate determination method remains to be decided.
Effects of ticagrelor monotherapy vs. clopidogrel monotherapy on platelet reactivity: a randomized, crossover clinical study (SINGLE study)
Published in Platelets, 2022
Meijiao He, Wei Yan, Yun Zhang, Yihui Kong, Xuejie Han, Jie Ren, Zhongyang Zhao, Guangzhong Liu, Jing Shi, Yue Li
Clopidogrel is a prodrug requiring cytochrome P450 (CYP) enzymes for its biotransformation into active thiol metabolite[23]. Ticagrelor is an orally administered, direct-acting, reversibly-binding P2Y12 receptor antagonist. The equilibrative nucleoside transporter 1 inhibition is rapidly absorbed and activated [24,25]. The PLATO trial [26], which enrolled 18,624 patients with ACS, demonstrated that ticagrelor significantly reduced the incidence of MACE, a composite of death from vascular causes, myocardial infarction, or stroke [569 (event rate at 360 days 9.0%) vs. 668 (10.7%); hazard ratio, 0.84; 95% confidence interval, 0.75–0.94; p = .0025]. Current guidelines favored the usage of ticagrelor 90 mg twice daily over clopidogrel 75 mg once daily in patients with CAD [27,28]. In our previous study, we found that low-dose ticagrelor provided greater platelet inhibition on ADP than clopidogrel in Chinese patients with CAD [29–32]. Therefore, ticagrelor was strongly recommended for patients with CAD compared with clopidogrel. Our study showed that ticagrelor and clopidogrel monotherapies provided platelet inhibition in the ADP-induced and AA-induced platelet aggregation, and ticagrelor monotherapy provided greater platelet inhibition than clopidogrel monotherapy. The result of our study confirmed the findings of previous studies. Ticagrelor monotherapy also provided a more rapid and powerful inhibition of AA-induced platelet aggregation than clopidogrel monotherapy.
Chemoresistance and resistance to targeted therapies in biliary tract cancer: what have we learned?
Published in Expert Opinion on Investigational Drugs, 2022
Christian Mayr, Tobias Kiesslich, Dominik Paul Modest, Sebastian Stintzing, Matthias Ocker, Daniel Neureiter
Regarding the standard chemotherapy protocols of BTC, the mechanism of reduced uptake is experimentally and clinically evident for gemcitabine, 5-FU, and cisplatin. The two families of concentrative nucleoside transporters (CNTs) (SLC28) and equilibrative nucleoside transporters (ENTs) (SLC29) physiologically perform the uptake of the nucleoside analogues gemcitabine and 5-fluorouracil [62]. In vitro experiments showed that mutation of ENT1 of BTC cell lines is definitively related to 5-FU resistance [59]. Additionally, ENT1 expression level is a predictive biomarker for a possible chemoresistance to gemcitabine in patients with advanced BTC [63]. Furthermore, the copper transporter CTR1 (SLC31A1), which is relevant for cisplatin uptake, is linked chemoresistance to cisplatin in vitro and in vivo [64].
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].