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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#1
John J Krais, Needa Virani, Partick H McKernan, Quang Nguyen, Kar-Ming Fung, Vassilios I Sikavitsas, Carla D Kurkjian, Roger G Harrison
Mutant cystathionine gamma-lyase was targeted to phosphatidylserine exposed on tumor vasculature through fusion with annexin A1 or annexin A5.  Cystathionine gamma-lyase E58N, R118L, and E338N mutations impart non-native methionine gamma-lyase activity, resulting in tumor-localized generation of highly toxic methylselenol upon systemic administration of non-toxic selenomethionine.  The described therapeutic system circumvents systemic toxicity issues using a novel drug delivery/generation approach and avoids the administration of non-native proteins and/or DNA required with other enzyme prodrug systems...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28459452/targeting-genomic-rearrangements-in-tumor-cells-through-cas9-mediated-insertion-of-a-suicide-gene
#2
Zhang-Hui Chen, Yan P Yu, Ze-Hua Zuo, Joel B Nelson, George K Michalopoulos, Satdatshan Monga, Silvia Liu, George Tseng, Jian-Hua Luo
Specifically targeting genomic rearrangements and mutations in tumor cells remains an elusive goal in cancer therapy. Here, we used Cas9-based genome editing to introduce the gene encoding the prodrug-converting enzyme herpes simplex virus type 1 thymidine kinase (HSV1-tk) into the genomes of cancer cells carrying unique sequences resulting from genome rearrangements. Specifically, we targeted the breakpoints of TMEM135-CCDC67 and MAN2A1-FER fusions in human prostate cancer or hepatocellular carcinoma cells in vitro and in mouse xenografts...
May 1, 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28457884/substrate-mediated-enzyme-prodrug-therapy
#3
REVIEW
Betina Fejerskov, Morten T Jarlstad Olesen, Alexander N Zelikin
Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs - individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner...
April 27, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28454453/targeting-assay-of-a-fusion-protein-applied-in-enzyme-prodrug-therapy
#4
Hao Wang, Jin-Jian Liu, Xiao-Liang Zhou
Tumor growth and metastasis are dependent on angiogenesis. The overexpression of integrin αvβ3 on angiogenic vessels and on numerous malignant human tumor cells suggests that these labeled ligands of integrin are potentially suitable for molecular imaging and in targeted therapy of tumors. In previous studies, we added a β-lactamase variant with reduced immunogenicity to the cyclic peptide RGD4C, resulting in the fusion protein RGD4CβL, which is suitable for use in targeted enzyme prodrug therapy (TEPT), a promising treatment for tumors...
April 2017: Oncology Letters
https://www.readbyqxmd.com/read/28446024/enhanced-vector-design-for-cancer-gene-therapy-with-hierarchical-enhancement-of-therapeutic-transgene-expression
#5
Maria B Kostina, Alexader V Sass, Elena A Stukacheva, Igor V Korobko, Eugeny D Sverdlov
A set of vectors for Cre recombinase-dependent expression of hybrid suicidal FCU1 transgene was constructed which included two-plasmid system where FCU1 and Cre transgenes reside in separate vectors, and single-plasmid variants when a single plasmid bears both transgenes. To improve safety profile and specificity in cancer gene therapy applications, as well as to assure stable propagation of plasmids in bacterial cells, Cre/LoxP system components were optimized. Bicistronic vector with Cre expression cassette placed between LoxP sites unidirectionally with FCU1 cDNA resulted in higher therapeutic efficiency compared to double-plasmid system in enzyme-prodrug suicide cancer gene therapy scheme...
April 27, 2017: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/28412325/designing-metal-contained-enzyme-mimics-for-prodrug-activation
#6
REVIEW
Baoji Du, Dan Li, Jin Wang, Erkang Wang
Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting the prodrugs into the drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on the natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization...
April 12, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28395199/design-synthesis-and-biological-evaluation-of-nad-p-h-quinone-oxidoreductase-nqo1-targeted-oridonin-prodrugs-possessing-indolequinone-moiety-for-hypoxia-selective-activation
#7
Shengtao Xu, Hong Yao, Lingling Pei, Mei Hu, Dahong Li, Yangyi Qiu, Guangyu Wang, Liang Wu, Hequan Yao, Zheying Zhu, Jinyi Xu
The enzyme NQO1 is a potential target for selective cancer therapy due to its overexpression in certain hypoxic tumors. A series of prodrugs possessing a variety of cytotoxic diterpenoids (oridonin and its analogues) as the leaving groups activated by NQO1 were synthesized by functionalization of 3-(hydroxymethyl)indolequinone, which is a good substrate of NQO1. The target compounds (29a-m) exhibited relatively higher antiproliferative activities against NQO1-rich human colon carcinoma cells (HT-29) and human lung carcinoma (A549) cells (IC50 = 0...
March 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28262557/engineering-a-multifunctional-nitroreductase-for-improved-activation-of-prodrugs-and-pet-probes-for-cancer-gene-therapy
#8
Janine N Copp, Alexandra M Mowday, Elsie M Williams, Christopher P Guise, Amir Ashoorzadeh, Abigail V Sharrock, Jack U Flanagan, Jeff B Smaill, Adam V Patterson, David F Ackerley
Gene-directed enzyme-prodrug therapy (GDEPT) is a promising anti-cancer strategy. However, inadequate prodrugs, inefficient prodrug activation, and a lack of non-invasive imaging capabilities have hindered clinical progression. To address these issues, we used a high-throughput Escherichia coli platform to evolve the multifunctional nitroreductase E. coli NfsA for improved activation of a promising next-generation prodrug, PR-104A, as well as clinically relevant nitro-masked positron emission tomography-imaging probes EF5 and HX4, thereby addressing a critical and unmet need for non-invasive bioimaging in nitroreductase GDEPT...
March 16, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28259838/enzyme-responsive-peptide-dendrimer-gemcitabine-conjugate-as-a-controlled-release-drug-delivery-vehicle-with-enhanced-antitumor-efficacy
#9
Chengyuan Zhang, Dayi Pan, Jin Li, Jiani Hu, Ashika Bains, Nicholas Guys, Hongyan Zhu, Xiaohui Li, Kui Luo, Qiyong Gong, Zhongwei Guc
Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycylphenylalanylleucylglycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h...
March 1, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28257943/photodynamic-therapy-enhances-the-efficacy-of-gene-directed-enzyme-prodrug-therapy
#10
Catherine Christie, Aftin Pomeroy, Rohit Nair, Kristian Berg, Henry Hirschberg
INTRODUCTION: Gene-directed enzyme prodrug therapy (GDEPT) employing the cytosine deaminase (CD) gene, which encodes an enzyme that converts the nontoxic agent 5-fluorocytosine (5-FC) into the chemotherapeutic drug 5-fluorouracil (5-FU), has shown promise both in experimental animals and in clinical trials. Nevertheless, with the transfection systems available presently the percentage of tumor cells incorporating the desired gene is usually too low for successful therapy. We have examined the ability of photodynamic therapy (PDT) to enhance the efficacy of the metabolites, converted from 5-FC by CD gene transfected rat glioma cells...
February 28, 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/28164519/angiotensin-converting-enzyme-inhibitors-influence-on-antiplatelet-therapy-of-clopidogrel-in-acs
#11
Shuo Yang, Chanjuan Cui, Jie Zhang, Rui Qiao
BACKGROUND: Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel. METHODS: We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28148846/tumor-homing-cytotoxic-human-induced-neural-stem-cells-for-cancer-therapy
#12
Juli R Bagó, Onyi Okolie, Raluca Dumitru, Matthew G Ewend, Joel S Parker, Ryan Vander Werff, T Michael Underhill, Ralf S Schmid, C Ryan Miller, Shawn D Hingtgen
Engineered neural stem cells (NSCs) are a promising approach to treating glioblastoma (GBM). The ideal NSC drug carrier for clinical use should be easily isolated and autologous to avoid immune rejection. We transdifferentiated (TD) human fibroblasts into tumor-homing early-stage induced NSCs (h-iNSC(TE)), engineered them to express optical reporters and different therapeutic gene products, and assessed the tumor-homing migration and therapeutic efficacy of cytotoxic h-iNSC(TE) in patient-derived GBM models of surgical and nonsurgical disease...
February 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28116598/enterolactone-glucuronide-and-%C3%AE-glucuronidase-in-antibody-directed-enzyme-prodrug-therapy-for-targeted-prostate-cancer-cell-treatment
#13
Yunyun Di, Shaoping Ji, Philipp Wolf, Ed S Krol, Jane Alcorn
Evidence from preclinical and animal studies demonstrated an anticancer effect of flaxseed lignans, particularly enterolactone (ENL), against prostate cancer. However, extensive first-pass metabolism following oral lignan consumption results in their systemic availability primarily as glucuronic acid conjugates (ENL-Gluc) and their modest in vivo effects. To overcome the unfavorable pharmacokinetics and improve their effectiveness in prostate cancer, antibody-directed enzyme prodrug therapy (ADEPT) might offer a novel strategy to allow for restricted activation of ENL from circulating ENL-Gluc within the tumor environment...
January 23, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28112512/enzyme-sensitive-and-amphiphilic-pegylated-dendrimer-paclitaxel-prodrug-based-nanoparticles-for-enhanced-stability-and-anticancer-efficacy
#14
Ning Li, Hao Cai, Lei Jiang, Jiani Hu, Ashika Bains, Jesse Hu, Qiyong Gong, Kui Luo, Zhongwei Gu
In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge...
March 1, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/28042530/enzyme-prodrug-systems-for-cancer-gene-therapy
#15
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
#16
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)...
January 28, 2017: 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
#17
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
#18
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...
February 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27986920/annexin-directed-%C3%AE-glucuronidase-for-the-targeted-treatment-of-solid-tumors
#19
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...
February 2017: 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
#20
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
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