Stefan Russmann, Ali Rahmany, David Niedrig, Karl-Dietrich Hatz, Katja Ludin, Andrea M Burden, Lars Englberger, Roland Backhaus, Andreas Serra, Markus Béchir
PURPOSE: The antiplatelet prodrug clopidogrel is bioactivated by the polymorphic enzyme CYP2C19. Prospective clinical studies demonstrated an association between CYP2C19 loss of function (LoF) variants and an increased risk of thrombotic events under clopidogrel, but pharmacogenetic (PGx) testing is not frequently implemented in clinical practice. We report our experience with PGx-guided clopidogrel therapy with particular regard to clinically relevant patient management changes. METHODS: We conducted an observational study analyzing patients that underwent PGx testing for clopidogrel therapy at two Swiss hospitals...
November 26, 2020: European Journal of Clinical Pharmacology
Seid Hamzic, Stefan Aebi, Markus Joerger, Michael Montemurro, Marc Ansari, Ursula Amstutz, Carlo Largiadèr
Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10–40% of patients experience severe, and in rare cases (0.2–0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by DPYD) are predictive of severe FP-related toxicities, and international clinical practice recommendations for DPYD genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available...
November 16, 2020: Swiss Medical Weekly
Tuğba Güngör, Esra Tokay, Ünzile Güven Gülhan, Nelin Hacıoğlu, Ayhan Çelik, Feray Köçkar, Mehmet Ay
In this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, 1 H NMR, 13 C NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell...
November 4, 2020: Bioorganic Chemistry
Gabrielle Romena, Lina Nguyen, Kristian Berg, Steen J Madsen, Henry Hirschberg
BACKGROUND: Drawn by tumor synthesis of chemo-attractive factors, macrophages are frequently found in and around glioblastomas and play an important role both in augmenting as well as inhibiting tumor growth. Patient-derived macrophages have the potential, therefore, to act as targeted delivery vectors for a variety of anti-cancer treatments. Among these is ex vivo gene transfection and re-injection back into the patient of macrophages to target residual tumors. In this study, photochemical internalization (PCI) is investigated as a technique for the non-viral transfection of the cytosine deaminase (CD) prodrug activating gene into macrophages...
November 11, 2020: Photodiagnosis and Photodynamic Therapy
Ramya Sree Boddu, Onkara Perumal, Divakar K
Nitroreductases, enzymes found mostly in bacteria and also in few eukaryotes, use nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor for their activity and metabolize an enormous list of diverse nitro group containing compounds. Nitroreductases capable of metabolizing nitroaromatic and nitro heterocyclic compounds have drawn great attention in recent years owing to their biotechnological, biomedical, environmental and human impact. These enzymes attracted medicinal chemists and pharmacologists because of their prodrug selectivity for activation/reduction of nitro compounds that wipe out pathogens/cancer cells, leaving the host/normal cells unharmed...
November 6, 2020: Biotechnology and Applied Biochemistry
Murtala A Ejalonibu, Ahmed A Elrashedy, Monsurat M Lawal, Hezekiel M Kumalo, Ndumiso N Mhlongo
The growing occurrence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains underscores an urgent need for new antibiotics. The development of more bioactive antibiotics against drug-resistant organisms with a different mode of action could be a game-changer for the cure and eradication of tuberculosis (TB). Pantothenate Kinase (PanK) and CTP synthetase (PyrG) are both essential for RNA, DNA, and Lipids biosynthesis pathways. Given the extensive knowledge on these biosynthesis pathways inhibition of Mtb growth and survival, these enzymes present a fascinating opportunity for anti-mycobacterial drug discovery...
November 6, 2020: Journal of Biomolecular Structure & Dynamics
Milica Markovic, Shimon Ben-Shabat, Arik Dahan
Prodrugs are bioreversible, inactive drug derivatives, which have the ability to convert into a parent drug in the body. In the past, prodrugs were used as a last option; however, nowadays, prodrugs are considered already in the early stages of drug development. Optimal prodrug needs to have effective absorption, distribution, metabolism, and elimination (ADME) features to be chemically stable, to be selective towards the particular site in the body, and to have appropriate safety. Traditional prodrug approach aims to improve physicochemical/biopharmaceutical drug properties; modern prodrugs also include cellular and molecular parameters to accomplish desired drug effect and site-specificity...
October 29, 2020: Pharmaceutics
Marwa O Mikati, Justin J Miller, Damon M Osbourn, Yasaman Barekatain, Naomi Ghebremichael, Ishaan T Shah, Carey-Ann D Burnham, Kenneth M Heidel, Victoria C Yan, Florian L Muller, Cynthia S Dowd, Rachel L Edwards, Audrey R Odom John
With the rising prevalence of multidrug resistance, there is an urgent need to develop novel antibiotics. Many putative antibiotics demonstrate promising in vitro potency but fail in vivo due to poor drug-like qualities (e.g., serum half-life, oral absorption, solubility, and toxicity). These drug-like properties can be modified through the addition of chemical protecting groups, creating "prodrugs" that are activated prior to target inhibition. Lipophilic prodrugging techniques, including the attachment of a pivaloyloxymethyl group, have garnered attention for their ability to increase cellular permeability by masking charged residues and the relative ease of the chemical prodrugging process...
October 29, 2020: ACS Infectious Diseases
Rasmus Ehren, Anne M Schijvens, Agnes Hackl, Michiel F Schreuder, Lutz T Weber
INTRODUCTION: Mycophenolate mofetil (MMF) is an ester prodrug of the immunosuppressant mycophenolic acid (MPA) and is recommended and widely used for maintenance immunosuppressive therapy in solid organ and stem-cell transplantation as well as in immunological kidney diseases. MPA is a potent, reversible, non-competitive inhibitor of the inosine monophosphate dehydrogenase (IMPDH), a crucial enzyme in the de novo purine synthesis in T- and B-lymphocytes, thereby inhibiting cell-mediated immunity and antibody formation...
October 27, 2020: Expert Opinion on Drug Metabolism & Toxicology
Susanne Berchtold, Julia Beil, Christian Raff, Irina Smirnow, Martina Schell, Janina D'Alvise, Silvia Gross, Ulrich M Lauer
Genetically modified vaccinia viruses (VACVs) have been shown to possess profound oncolytic capabilities. However, tumor cell resistance to VACVs may endanger broad clinical success. Using cell mass assays, viral replication studies, and fluorescence microscopy, we investigated primary resistance phenomena of cell lines of the NCI-60 tumor cell panel to GLV-1h94, a derivative of the Lister strain of VACV, which encodes the enzyme super cytosine deaminase (SCD) that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU)...
October 15, 2020: International Journal of Molecular Sciences
Sudhir Raghavan, David S Baskin, Martyn A Sharpe
We previously reported the in vitro and in vivo efficacy of N,N-bis(2-chloroethyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)propenamide, a prodrug that targeted the mitochondria of glioblastoma (GBM). The mitochondrial enzyme monoamine oxidase B (MAOB) is highly expressed in GBM and oxidizes an uncharged methyl-tetrahydropyridine (MP-) moiety into the mitochondrially-targeted cationic form, methyl-pyridinium (P+-). Coupling this MAOB-sensitive group to a nitrogen mustard produced a prodrug that damaged GBM mitochondria and killed GBM cells...
October 8, 2020: Molecular Cancer Therapeutics
Patrick Ball, Jennifer Halliwell, Simon Anderson, Vanessa Gwenin, Christopher Gwenin
Directed enzyme prodrug therapy (DEPT) is a cancer chemotherapy strategy in which bacterial enzymes are delivered to a cancer site before prodrug administration, resulting in prodrug activation at the cancer site and more localized treatment. A major limitation to DEPT is the poor effectiveness of the most studied enzyme for the CB1954 prodrug, NfnB from Escherichia coli, at concentrations suitable for human use. Much research into finding alternative enzymes to NfnB has resulted in the identification of the Xenobiotic reductases, XenA and XenB, which have been shown in the literature to reduce environmentally polluting nitro-compounds...
September 26, 2020: MicrobiologyOpen
Iman Sherif
One of the widely used anticancer drugs for the treatment of various neoplasms is cyclophosphamide (CYP). The inactive prodrug CYP is metabolized by cytochrome P450 enzyme into active metabolites, phosphoramide mustard and acrolein. The accumulation of acrolein metabolite inside the urothelium results in hemorrhagic cystitis (HC) which is a urotoxic adverse effect associated with the use of CYP. To counteract the occurrence of HC induced by CYP, Mesna is usually used, with allergic reactions reported in some cases...
July 2020: Acta Scientiarum Polonorum. Technologia Alimentaria
Janine N Copp, Daniel Pletzer, Alistair S Brown, Joris Van der Heijden, Charlotte M Miton, Rebecca J Edgar, Michelle H Rich, Rory F Little, Elsie M Williams, Robert E W Hancock, Nobuhiko Tokuriki, David F Ackerley
One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies...
September 15, 2020: MBio
Alexandra Marie Mowday, Janine Naomi Copp, Sophie Philippa Syddall, Ludwig Jerome Dubois, Jingli Wang, Natasja Gabi Lieuwes, Rianne Biemans, Amir Ashoorzadeh, Maria Rosaria Abbattista, Elsie May Williams, Christopher Paul Guise, Philippe Lambin, David Francis Ackerley, Jeff Bruce Smaill, Jan Theys, Adam Vorn Patterson
The use of reporter genes to non-invasively image molecular processes inside cells has significant translational potential, particularly in the context of systemically administered gene therapy vectors and adoptively administered cells such as immune or stem cell based therapies. Bacterial nitroreductase enzymes possess ideal properties for reporter gene imaging applications, being of non-human origin and possessing the ability to metabolize a range of clinically relevant nitro(hetero)cyclic substrates. Methods: A library of eleven Escherichia coli nitroreductase candidates were screened for the ability to efficiently metabolize 2-nitroimidazole based positron emission tomography (PET) probes originally developed as radiotracers for hypoxic cell imaging...
2020: Theranostics
Geraldine Xue En Tu, Yoon Khei Ho, Zhi Xu Ng, Ke Jia Teo, Tseng Tsai Yeo, Heng-Phon Too
BACKGROUND: Mesenchymal stem cells (MSCs) serve as an attractive vehicle for cell-directed enzyme prodrug therapy (CDEPT) due to their unique tumour-nesting ability. Such approach holds high therapeutic potential for treating solid tumours including glioblastoma multiforme (GBM), a devastating disease with limited effective treatment options. Currently, it is a common practice in research and clinical manufacturing to use viruses to deliver therapeutic genes into MSCs. However, this is limited by the inherent issues of safety, high cost and demanding manufacturing processes...
September 11, 2020: Stem Cell Research & Therapy
Yoon Khei Ho, Jun Yung Woo, Geraldine Xue En Tu, Lih-Wen Deng, Heng-Phon Too
Mesenchymal stem cells (MSCs) driven gene-directed enzyme prodrug therapy has emerged as a potential strategy for cancer treatment. The tumour-nesting properties of MSCs enable these vehicles to target tumours and metastases with effective therapies. A crucial step in engineering MSCs is the delivery of genetic material with low toxicity and high efficiency. Due to the low efficiency of current transfection methods, viral vectors are used widely to modify MSCs in preclinical and clinical studies. We show, for the first time, the high transfection efficiency (> 80%) of human adipose tissue derived-MSCs (AT-MSCs) using a cost-effective and off-the-shelf Polyethylenimine, in the presence of histone deacetylase 6 inhibitor and fusogenic lipids...
August 31, 2020: Scientific Reports
Han Young Kim, Sang Hoon Um, Yejin Sung, Man Kyu Shim, Suah Yang, Jooho Park, Eun Sun Kim, Kwangmeyung Kim, Ick Chan Kwon, Ju Hee Ryu
One of the most promising approaches for the treatment of colorectal cancer is targeting epidermal growth factor receptor (EGFR). Comprehensive research has led to significant clinical outcomes using EGFR-targeted anticancer drugs; however, the response to these drugs still largely varies among individuals. The current diagnostic platform provides limited information that does not enable successful prediction of the anticancer performance of EGFR-targeted drugs. Here, we developed a EGFR-targeted activatable probe for predicting therapeutic efficacy of EGFR-targeted doxorubicin prodrug in colorectal cancer therapy...
August 28, 2020: Journal of Controlled Release
Michelle H Rich, Abigail V Sharrock, Amir Ashoorzadeh, Adam V Patterson, Jeff B Smaill, David F Ackerley
OBJECTIVES: To use directed evolution to improve YfkO-mediated reduction of the 5-nitroimidazole PET-capable probe SN33623 without impairing conversion of the anti-cancer prodrug CB1954. RESULTS: Two iterations of error-prone PCR, purifying selection, and FACS sorting in a DNA damage quantifying GFP reporter strain were used to identify three YfkO variants able to sensitize E. coli host cells to at least 2.4-fold lower concentrations of SN33623 than the native enzyme...
August 26, 2020: Biotechnology Letters
Megan N Gower, Lindsay R Ratner, Alexis K Williams, Joseph S Rossi, George A Stouffer, Craig R Lee
In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke...
2020: Pharmacogenomics and Personalized Medicine
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