Browsing by Subject "5-FLUOROURACIL"

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  • de Luca, Sergio; Seal, Prasenjit; Parekh, Harendra S.; Tupally, Karnaker R.; Smith, Sean C. (2020)
    The mechanism by which cell-penetrating peptides and antimicrobial peptides cross plasma membranes is unknown, as is how cell-penetrating peptides facilitate drug delivery, mediating the transport of small molecules. Once nondisruptive and nonendocytotic pathways are excluded, pore formation is one of the proposed mechanisms, including toroidal, barrel-stave, or carpet models. Spontaneous pores are observed in coarse-grained simulations and less often in molecular dynamics simulations. While pores are widely assumed and inferred, there is no unambiguous experimental evidence of the existence of pores. Some recent experimental studies contradict the mechanistic picture of pore formation, however, highlighting the possibility of a direct translocation pathway that is both nondisruptive and nonendocytotic. In this work, a model is proposed a model for peptide (linear and dendritic) translocation which does not require the presence of pores and which potentially accords with such experiments. It is suggested that a charged peptide, as it experiences an increasingly hydrophobic environment within the membrane surface, can utilize a proton chain transfer mechanism to shed its protons to counter ions or potentially phospholipid head groups in the membrane skin region, thereby becoming compatible with the hydrophobic interior of the membrane. This increases the likelihood to move into the highly hydrophobic core of the membrane and ultimately reach the opposite leaflet to re-acquire protons again, suggesting a potential "chameleon" mechanism for non-disruptive and non-endocytotic membrane translocation. The molecular dynamics simulations reveal stability of peptide bridges joining two membrane leaflets and demonstrate that this can facilitate cross-membrane transport of small drug molecules.
  • Marwah, Megha; Magarkar, Aniket; Ray, Debes; Aswal, Vinod; Bunker, Alex; Nagarsenker, Mangal (2018)
    Glyceryl monostearate (GMS) is a single-tailed lipidic monoglyceride commonly used as a nontoxic food additive. In this study, we have investigated GMS, specifically its self-assembling properties and subsequent application in drug delivery. Results from in silico modeling, corroborated by complementary small-angle neutron scattering, demonstrated vesicle formation; associated phase transitions were analyzed using differential scanning calorimetry; dynamic light scattering revealed particle size alterations that occurred in the transition region. Spherical morphology of unilamellar vesicles was visualized using transmission electron microscopy imaging. Further, hydrophilic and hydrophobic drug loading in GMS vesicles and their amenability to surface modification for hepatic targeting have, in this study, been both predicted through molecular simulation study and demonstrated experimentally. The influence of hepatotropic ligands on the stability of drug-loaded GMS vesicles vis-a-vis cholesterol has also been investigated; the resulting GMS-based drug delivery vehicle, its properties enhanced through surface decoration, is envisaged to achieve targeted delivery of its payload to hepatocytes.
  • Scott, Timothy A.; Quintaneiro, Leonor M.; Norvaisas, Povilas; Lui, Prudence P.; Wilson, Matthew P.; Leung, Kit-Yi; Herrera-Dominguez, Lucia; Sudiwala, Sonia; Pessia, Alberto; Clayton, Peter T.; Bryson, Kevin; Velagapudi, Vidya; Mills, Philippa B.; Typas, Athanasios; Greene, Nicholas D. E.; Cabreiro, Filipe (2017)
    Fluoropyrimidines are the first-line treatment for colorectal cancer, but their efficacy is highly variable between patients. We queried whether gut microbes, a known source of inter-individual variability, impacted drug efficacy. Combining two tractable genetic models, the bacterium E. coli and the nematode C. elegans, we performed three-way high-throughput screens that unraveled the complexity underlying host-microbe-drug interactions. We report that microbes can bolster or suppress the effects of fluoropyrimidines through metabolic drug interconversion involving bacterial vitamin B-6, B-9, and ribonucleotide metabolism. Also, disturbances in bacterial deoxynucleotide pools amplify 5-FU-induced autophagy and cell death in host cells, an effect regulated by the nucleoside diphosphate kinase ndk-1. Our data suggest a two-way bacterial mediation of fluoropyrimidine effects on host metabolism, which contributes to drug efficacy. These findings highlight the potential therapeutic power of manipulating intestinal microbiota to ensure host metabolic health and treat disease.
  • Adam, Rene; Yi, Bin; Innominato, Pasquale F.; Barroso, Eduardo; Laurent, Christophe; Giuliante, Felice; Capussotti, Lorenzo; Lapointe, Real; Regimbeau, Jean-Marc; Lopez-Ben, Santiago; Isoniemi, Helena; Hubert, Catherine; Lin, Jen-Kou; Gruenberger, Thomas; Elias, Dominique; Skipenko, Oleg G.; Guglielmi, Alfredo; LiverMetSurvey Int Contributing (2017)
    Purpose: Patient outcome after resection of colorectal liver metastases (CLM) following second-line preoperative chemotherapy (PCT) performed for insufficient response or toxicity of the first-line, is little known and has here been compared to the outcome following first-line. Patients and methods: From January 2005 to June 2013, 5624 and 791 consecutive patients of a prospective international cohort received 1 and 2 PCT lines before CLM resection (group 1 and 2, respectively). Survival and prognostic factors were analysed. Results: After a mean follow-up of 30.1 months, there was no difference in survival from CLM diagnosis (median, 3-, and 5-year overall survival [OS]: 58.6 months, 76% and 49% in group 2 versus 58.9 months, 71% and 49% in group 1, respectively, P = 0.32). After hepatectomy, disease-free survival (DFS) was however shorter in group 2: 17.2 months, 27% and 15% versus 19.4 months, 32% and 23%, respectively (P = 0.001). Among the initially unresectable patients of group 1 and 2, no statistical difference in OS or DFS was observed. Independent predictors of worse OS in group 2 were positive primary lymph nodes, extrahepatic disease, tumour progression on second line, R2 resection and number of hepatectomies/year Conclusion: CLM resection following second-line PCT, after oncosurgically favourable selection, could bring similar OS compared to what observed after first-line. For initially unresectable patients, OS or DFS is comparable between first-and second-line PCT. Surgery should not be denied after the failure of first-line chemotherapy. (C) 2017 Elsevier Ltd. All rights reserved.