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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).
Antiviral Treatment
Published in Marie Studahl, Paola Cinque, Tomas Bergström, Herpes Simplex Viruses, 2017
The precursor or prodrugs valacyclovir (8–10) and famciclovir (11–13) are converted to the respective nucleoside analogues acyclovir and penciclovir (Figs. 1 and 2) by esterases of the intestinal mucosa and first pass of the liver [esterases and aldehyde oxidase in the case of FCV to convert 6-deoxy-PCV (BRL42569) to PCV]. Acyclovir is transported into cells by passive diffusion or by a nucleoside transporter and subsequent phosphorylation traps the nucleosides in cells (Fig. 2). The intracellular half-life of ACVTP is ~0.7 (up to 2.5) hours versus 10–12 hours for PCYTP. In tissue culture, the relative potency of inhibition of herpesvirus replication is HSV-1 (IC50 ~0.5– 1μΜ) < HSV-2 (IC50 ~2–μΜ) < EBV (IC50 ~0.5-5 μΜ) < VZV (IC50 ~5-20 μΜ) ≪ HCMV (IC50 ~20–200 μΜ) for ACV.
Precise engineering of Gemcitabine prodrug cocktails into single polymeric nanoparticles delivery for metastatic thyroid cancer cells
Published in Drug Delivery, 2020
Chenggong Liu, Qiongmei Han, Hua Liu, Cuirong Zhu, Wei Gui, Xiaodong Yang, Wansen Li
After successful synthesis of GEM-NPs, we performed the CCK-8 (cell counting kit-8) examinations to evaluate the cytotoxicity of the GEM and GEM-NPs to thyroid cancer cell lines, with B-CPAP and FTC-133 cancer cells. Next, on treatment with the medications for 24 h, the viability of the cells was monitored, and the half inhibitory concentration (IC50) was obtained from the dose-dependent curve (Figure 4). Encouragingly, compared with the free drug, prodrug-assembled nanoparticles showed substantially enhanced cytotoxic activity in both tested cell lines. For instance, in B-CPAP cell lines, the IC50 was 138.40 ± 11.12 and 13.62 ± 0.97 for GEM and GEM-NPs, respectively. In FTC-133 cell lines, the IC50 was 62.63 ± 3.30 and 25.16 ± 2.80 for GEM and GEM-NPs, respectively. Further, using free LA–GEM conjugate to test the cytotoxicity, we confirmed that PUFAylation of GEM at the 4-(N)-position indeed did not impair the potency of GEM. After entering the cells, the amide bond could be hydrolyzed by intracellular amidases such as cathepsin B or cathepsin D, thereby regenerating active GEM. GEM is a hydrophilic molecule; thus, it is difficult to diffuse through the lipid bilayer of the cell membrane. Therefore, efficient cellular uptake requires membrane nucleoside transporter proteins.
Inhibitor selectivity of CNTs and ENTs
Published in Xenobiotica, 2019
Balázs Vaskó, Viktória Juhász, Beáta Tóth, Anita Kurunczi, Zsolt Fekete, Joseph Krisjanis Zolnerciks, Emese Kis, Rémi Magnan, Axel Bidon-Chanal Badia, Marçal Pastor-Anglada, Eszter Hazai, Zsolt Bikadi, Ferenc Fülöp, Peter Krajcsi
The human CNT family consists of three members, CNT1–3, which are all localized to the plasma membrane. In contrast, of the four members of the ENT family, only ENT1 and ENT2 are unequivocally implicated in translocation of nucleosides across the plasma membrane (Endo et al., 2007). Specificity of nucleoside transporters is usually categorized based on the nature of the base, purine or pyrimidine (Fernandez-Calotti et al., 2011). This suggests that even inhibitory interactions are mainly defined by the nature of the base. We, therefore, studied interaction of nucleoside analogs with these five nucleoside transporters, allowing for a comparison of specificity across the whole nucleoside transporter panel. To explore the relative role of the base and the monosaccharide moiety we selected compounds that either harbor an arabinose or a cytosine moiety (or both, such as ara-C), as these were the families with relatively large, commercially available drug members. In addition, this study is unique in that we expressed the transporters using the same cellular background so as to reduce or even eliminate the effect of an important covariate, the membrane microenvironment (Volonte & D’Ambrosi, 2009). Furthermore, post-translational regulation due to protein–protein associations as well as phosphorylation are likely similar in these cell lines expressing the different nucleoside transporters.
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
One of the main steps for a drug to exert its cytotoxicity, as for other nucleoside analogs, is the uptake into the cell. This is mediated by the human equilibrative nucleoside transporter (hENT) and the human concentrative nucleoside transporter (hCNT) family [19]. An inhibitor of ENT1, dipyridamole, reduced sensitivity against RX-3117, indicating that hENT1 was responsible for uptake of the drug (similarly to gemcitabine), possibly excluding other transporters [12]. A cell line deficient in hENT1 and lacking other transporters was also resistant to RX-3117 (Figure 3).