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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28042530/enzyme-prodrug-systems-for-cancer-gene-therapy
#1
Obeid M Malekshah, Xuguang Chen, Alireza Nomani, Siddik Sarkar, Arash Hatefi
The use of enzyme/prodrug system has gained attention because it could help improve the efficacy and safety of conventional cancer chemotherapies. In this approach, cancer cells are first transfected with a gene that can express an enzyme with ability to convert a non-toxic prodrug into its active cytotoxic form. As a result, the activated prodrug could kill the transfected cancer cells. Despite the significant progress of different suicide gene therapy protocols in preclinical studies and early clinical trials, none has reached the clinic due to several shortcomings...
December 2016: Current Pharmacology Reports
https://www.readbyqxmd.com/read/28017891/self-immolative-nanoparticles-for-simultaneous-delivery-of-microrna-and-targeting-of-polyamine-metabolism-in-combination-cancer-therapy
#2
Ying Xie, Tracy Murray-Stewart, Yazhe Wang, Fei Yu, Jing Li, Laurence J Marton, Robert A Casero, David Oupický
Combination of anticancer drugs with therapeutic microRNA (miRNA) has emerged as a promising anticancer strategy. However, the promise is hampered by a lack of desirable delivery systems. We report on the development of self-immolative nanoparticles capable of simultaneously delivering miR-34a mimic and targeting dysregulated polyamine metabolism in cancer. The nanoparticles were prepared from a biodegradable polycationic prodrug, named DSS-BEN, which was synthesized from a polyamine analog N(1),N(11)-bisethylnorspermine (BENSpm)...
December 23, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28005335/tumor-specific-multiple-stimuli-activated-dendrimeric-nanoassemblies-with-metabolic-blockade-surmount-chemotherapy-resistance
#3
Yachao Li, Xianghui Xu, Xiao Zhang, Yunkun Li, Zhijun Zhang, Zhongwei Gu
Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs...
December 27, 2016: ACS Nano
https://www.readbyqxmd.com/read/27986921/development-of-a-cancer-marker-activated-enzymatic-switch-from-the-herpes-simplex-virus-thymidine-kinase
#4
Nirav Y Shelat, Sidhartha Parhi, Marc Ostermeier
Discovery of new cancer biomarkers and advances in targeted gene delivery mechanisms have made gene-directed enzyme prodrug therapy (GDEPT) an attractive method for treating cancer. Recent focus has been placed on increasing target specificity of gene delivery systems and reducing toxicity in non-cancer cells in order to make GDEPT viable. To help address this challenge, we have developed an enzymatic switch that confers higher prodrug toxicity in the presence of a cancer marker. The enzymatic switch was derived from the herpes simplex virus thymidine kinase (HSV-TK) fused to the CH1 domain of the p300 protein...
December 15, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27986920/annexin-directed-%C3%AE-glucuronidase-for-the-targeted-treatment-of-solid-tumors
#5
Katrin P Guillen, Eliza A Ruben, Needa Virani, Roger G Harrison
Enzyme prodrug therapy has the potential to remedy the lack of selectivity associated with the systemic administration of chemotherapy. However, most current systems are immunogenic and constrained to a monotherapeutic approach. We developed a new class of fusion proteins centered about the human enzyme β-glucuronidase (βG), capable of converting several innocuous prodrugs into chemotherapeutics. We targeted βG to phosphatidylserine on tumor cells, tumor vasculature and metastases via annexin A1/A5. Phosphatidylserine shows promise as a universal marker for solid tumors and allows for tumor type-independent targeting...
December 15, 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27986535/reduction-of-quinones-and-nitroaromatic-compounds-by-escherichia-coli-nitroreductase-a-nfsa-characterization-of-kinetics-and-substrate-specificity
#6
Benjaminas Valiauga, Elsie M Williams, David F Ackerley, Narimantas Čėnas
NfsA, a major FMN-associated nitroreductase of E. coli, reduces nitroaromatic compounds via consecutive two-electron transfers. NfsA has potential applications in the biodegradation of nitroaromatic environment pollutants, e.g. explosives, and is also of interest for the anticancer strategy gene-directed enzyme prodrug therapy. However, the catalytic mechanism of NfsA is poorly characterized. Here we examined the NADPH-dependent reduction of quinones (n = 16) and nitroaromatic compounds (n = 12) by NfsA...
January 15, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/27974807/long-term-neprilysin-inhibition-implications-for-arnis
#7
REVIEW
Duncan J Campbell
Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015...
December 15, 2016: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/27966832/design-of-block-copolymer-micellar-aggregates-for-co-delivery-of-enzyme-and-anticancer-prodrug
#8
Hongping Li, Lulu Chen, Yuting Shi, Binbin Yuan, Yingxia Ma, Hua Wei, Guanghui Zhao
Traditional enzyme-prodrug therapy (EPT) is a two-step strategy, which has many serious deficiencies, so having a one-step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co-delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3-indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG-PAsp(AED)-CA consisting of poly(ethylene glycol) (PEG), reduction-sensitive poly (N-(2,2'-dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction-sensitive interlayer...
December 14, 2016: Chemistry, An Asian Journal
https://www.readbyqxmd.com/read/27754187/sp-04-2-lcz-696-a-new-paradigm-shift-for-the-treatment-of-heart-failure
#9
ByungSu Yoo
Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. The cornerstone of modern drug therapy in chronic HF is the inhibition of neurohormonal activation that plays a crucial role in the pathophysiology of HF development and progression and, more specifically, of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. LCZ696 is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril)...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27749047/stimulus-responsive-prochelators-for-manipulating-cellular-metals
#10
Qin Wang, Katherine J Franz
Metal ions are essential for a wide range of physiological processes, but they can also be toxic if not appropriately regulated by a complex network of metal trafficking proteins. Intervention in cellular metal distribution with small-molecule or peptide chelating agents has promising therapeutic potential to harness metals to fight disease. Molecular outcomes associated with forming metal-chelate interactions in situ include altering the concentration and subcellular metal distribution, inhibiting metalloenzymes, enhancing the reactivity of a metal species to elicit a favorable biological response, or passivating the reactivity of a metal species to prevent deleterious reactivity...
November 15, 2016: Accounts of Chemical Research
https://www.readbyqxmd.com/read/27737561/translating-antibody-directed-enzyme-prodrug-therapy-adept-and-prospects-for-combination
#11
Surinder K Sharma, Kenneth D Bagshawe
The generation of cytotoxic drugs, selectively within tumours, from non-toxic prodrugs by targeted enzymes provides a powerful system for cancer therapy. In the form of Antibody directed enzyme prodrug therapy (ADEPT), this approach has shown feasibility in the clinic. Areas covered: Although numerous enzyme prodrug combinations have been reported over the last two decades, only the CPG2 ADEPT system has progressed to clinical trials. Using readily available components such as chemical antibody enzyme conjugate or recombinant multifunctional fusion protein, delivery of a specific enzyme to tumours, its elimination from non-tumour sites and prodrug activation has been achieved with therapeutic benefit in the clinic...
January 2017: Expert Opinion on Biological Therapy
https://www.readbyqxmd.com/read/27706901/targeting-a-targeted-drug-an-approach-toward-hypoxia-activatable-tyrosine-kinase-inhibitor-prodrugs
#12
Claudia Karnthaler-Benbakka, Diana Groza, Bettina Koblmüller, Alessio Terenzi, Katharina Holste, Melanie Haider, Dina Baier, Walter Berger, Petra Heffeter, Christian R Kowol, Bernhard K Keppler
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture...
October 5, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27687310/vectorized-gene-therapy-of-liver-tumors-proof-of-concept-of-tg4023-mva-fcu1-in-combination-with-flucytosine
#13
F Husseini, J-P Delord, C Fournel-Federico, J Guitton, P Erbs, M Homerin, C Halluard, C Jemming, C Orange, J-M Limacher, J-E Kurtz
BACKGROUND: TG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5'-monophosphate (5-FUMP), respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intra-tumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors...
September 29, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27643822/new-perspectives-in-the-treatment-of-advanced-gastric-cancer-s-1-as-a-novel-oral-5-fu-therapy-in-combination-with-cisplatin
#14
Rolf Mahlberg, Sylvie Lorenzen, Peter Thuss-Patience, Volker Heinemann, Per Pfeiffer, Markus Möhler
Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events...
2017: Chemotherapy
https://www.readbyqxmd.com/read/27643144/sp-04-2-lcz-696-a-new-paradigm-shift-for-the-treatment-of-heart-failure
#15
ByungSu Yoo
Heart failure (HF) represents a significant healthcare issue because of its ever-increasing prevalence, poor prognosis and complex pathophysiology. The cornerstone of modern drug therapy in chronic HF is the inhibition of neurohormonal activation that plays a crucial role in the pathophysiology of HF development and progression and, more specifically, of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. LCZ696 is a first-in-class, angiotensin receptor NEP inhibitor (ARNI) that consists of a supramolecular complex of a molecule of the ARB valsartan in combination with a molecule of the NEP inhibitor prodrug AHU377 (also known as sacubitril)...
September 2016: Journal of Hypertension
https://www.readbyqxmd.com/read/27598485/human-cytochrome-p450-2w1-is-not-expressed-in-adrenal-cortex-and-is-only-rarely-expressed-in-adrenocortical-carcinomas
#16
Paola Nolé, Britt Duijndam, Adam Stenman, C Christofer Juhlin, Mikael Kozyra, Catharina Larsson, Magnus Ingelman-Sundberg, Inger Johansson
Human cytochome P450 2W1 (CYP2W1) enzyme is expressed in fetal colon and in colon tumors. The level of expression is higher in colon metastases than in the parent tumors and the enzyme is a possible drug target for treatment of colorectal cancer, as demonstrated in mouse xenograft studies. A previous study published in this journal reported that CYP2W1 is highly expressed in normal and transformed adrenal tissue. However, adrenal expression of CYP2W1 protein was not seen in previous studies in our research group...
2016: PloS One
https://www.readbyqxmd.com/read/27573048/current-treatments-for-advanced-melanoma-and-introduction-of-a-promising-novel-gene-therapy-for-melanoma-review
#17
Jae-Rim Heo, Nam-Hyung Kim, Jaejin Cho, Kyung-Chul Choi
Metastatic melanoma is a fatal form of skin cancer that has a tendency to proliferate more rapidly than any other solid tumor. Since 2010, treatment options for metastatic melanoma have been developed including chemotherapies, checkpoint inhibition immunotherapies, e.g., anti‑cytotoxic T‑lymphocyte antigen‑4 (CTLA‑4) and anti‑programmed death‑1 (PD‑1), and molecular-targeted therapies, e.g., BRAF and MEK inhibitors. These treatments have shown not only high response rates yet also side‑effects and limitations...
October 2016: Oncology Reports
https://www.readbyqxmd.com/read/27568924/preclinical-evaluation-of-a-mercaptobenzamide-and-its-prodrug-for-ncp7-targeted-inhibition-of-human-immunodeficiency-virus
#18
T L Hartman, L Yang, A N Helfrick, M Hassink, N I Shank, K George Rosenker, M T Scerba, M Saha, E Hughes, A Q Wang, X Xu, P Gupta, R W Buckheit, D H Appella
Although the effective use of highly active antiretroviral therapy results in the suppression of virus production in infected individuals, it does not eliminate the infection and low level virus production in cells harboring virus in sanctuary sites. Thus, the continued search for new antiretroviral agents with unique and different mechanisms of HIV inhibition remains critical, and compounds that can reduce the level of virus production from cells already infected with HIV, as opposed to preventing de novo infection, would be of great benefit...
October 2016: Antiviral Research
https://www.readbyqxmd.com/read/27558786/insight-into-prodrugs-of-quinolones-and-fluoroquinolones
#19
Prabodh Chander Sharma, Mona Piplani, Monika Mittal, Rakesh Pahwa
Quinolones and fluoroquinolones are principal weapons against variety of bacterial infections and exert their antibacterial potential by interfering the activities of bacterial enzymes. As these agents are associated with some limitations, an important approach to overcome these major constraints is to prepare covalent derivatives, i.e. prodrugs. Prodrug design has been employed to improve the limitations of these drugs such as less aqueous solubility, poor absorption and distribution, toxicity, disagreeable taste, poor lipophilicity etc and for improving their pharmacological profile...
2016: Infectious Disorders Drug Targets
https://www.readbyqxmd.com/read/27527860/her2-oncogene-transformation-enhances-5-aminolevulinic-acid-mediated-protoporphyrin-ix-production-and-photodynamic-therapy-response
#20
Xue Yang, Pratheeba Palasuberniam, Kenneth A Myers, Chenguang Wang, Bin Chen
Enhanced protoporphyrin IX (PpIX) production in tumors derived from the administration of 5-aminolevulinic acid (ALA) enables the use of ALA as a prodrug for photodynamic therapy (PDT) and fluorescence-guided tumor resection. Although ALA has been successfully used in the clinic, the mechanism underlying enhanced ALA-induced PpIX production in tumors is not well understood. Human epidermal growth receptor 2 (Her2, Neu, ErbB2) is a driver oncogene in human cancers, particularly breast cancers. Here we showed that, in addition to activating Her2/Neu cell signaling, inducing epithelial-mesenchymal transition and upregulating glycolytic enzymes, transfection of NeuT (a mutated Her2/Neu) oncogene in MCF10A human breast epithelial cells significantly enhanced ALA-induced PpIX fluorescence by elevating some enzymes involved in PpIX biosynthesis...
September 6, 2016: Oncotarget
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