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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28627471/phospholipid-drug-conjugates-as-a-novel-oral-drug-targeting-approach-for-the-treatment-of-inflammatory-bowel-disease
#1
Arik Dahan, Milica Markovic, Svetlana Epstein, Noa Cohen, Ellen M Zimmermann, Aaron Aponick, Shimon Ben-Shabat
The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied...
June 13, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28602669/the-selective-cytotoxicity-of-new-triazene-compounds-to-human-melanoma-cells
#2
Ana Sousa, Fábio Santos, Maria Manuela Gaspar, Susana Calado, João D Pereira, Eduarda Mendes, Ana Paula Francisco, Maria Jesus Perry
Metastatic melanoma still remains one the most difficult cancers to overcome. The aim of our research was the design of anti-tumour triazene compounds 3 for application to a melanoma-specific therapy. The strategy exploits the unique enzyme pathway of melanin biosynthesis for conversion of non-toxic prodrugs into toxic drugs in the melanoma cell. The compounds 3 were designed by coupling two active moieties, the alkylating triazenes and different tyrosinase substrates. All compounds 3 revealed to be chemically stable in isotonic phosphate buffer (PBS) at physiologic pH (t½≥48h), and most of them showed to be slowly hydrolysed in human plasma (1...
May 31, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28589082/genetically-engineered-vaccinia-viruses-as-agents-for-cancer-treatment-imaging-and-transgene-delivery
#3
REVIEW
Dana Haddad
Despite advances in technology, the formidable challenge of treating cancer, especially if advanced, still remains with no significant improvement in survival rates, even with the most common forms of cancer. Oncolytic viral therapies have shown great promise for the treatment of various cancers, with the possible advantages of stronger treatment efficacy compared to conventional therapy due to higher tumor selectivity, and less toxicity. They are able to preferentially and selectively propagate in cancer cells, consequently destroying tumor tissue mainly via cell lysis, while leaving non-cancerous tissues unharmed...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28582716/combination-of-active-targeting-enzyme-triggered-release-and-fluorescent-dye-into-gold-nanoclusters-for-endomicroscopy-guided-photothermal-photodynamic-therapy-to-pancreatic-ductal-adenocarcinoma
#4
Hui Li, Ping Wang, Yunxiang Deng, Meiying Zeng, Yan Tang, Wei-Hong Zhu, Yingsheng Cheng
Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating malignancies in patients, and there is an urgent need for an effective treatment method. Herein, we report a novel gold nanocluster-based platform for confocal laser endomicroscopy-guided photothermal therapy (PTT)/photodynamic therapy (PDT) for PDAC, which consists of four components: the PTT-carrier gold nanocluster, an active targeting ligand U11 peptide, a Cathepsin E (CTSE)-sensitive PDT therapy prodrug, and a CTSE-sensitive imaging agent (cyanine dye Cy5...
September 2017: Biomaterials
https://www.readbyqxmd.com/read/28580145/lysosome-oriented-dual-stage-ph-responsive-polymeric-micelles-for-%C3%AE-lapachone-delivery
#5
Yinjian Zhou, Ying Dong, Gang Huang, Yiguang Wang, Xiaonan Huang, Fayun Zhang, David A Boothman, Jinming Gao, Wei Liang
β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage...
December 14, 2016: Journal of Materials Chemistry. B, Materials for Biology and Medicine
https://www.readbyqxmd.com/read/28566438/in-vivo-antitumoral-efficacy-of-phac-algp-doxorubicin-an-enzyme-activated-doxorubicin-prodrug-in-patient-derived-soft-tissue-sarcoma-xenograft-models
#6
Jasmien Cornillie, Agnieszka Wozniak, Peter Pokreisz, Andrea Casazza, Lise Vreys, Jasmien Wellens, Ulla Vanleeuw, Yemarshet K Gebreyohannes, Maria Debiec-Rychter, Raf Sciot, Daphne Hompes, Patrick Schöffski
Given the very limited efficacy of doxorubicin (doxo) in soft tissue sarcoma, there is a clear need for more active and less toxic treatments for this family of diseases. However, due to the rarity of these malignancies and lack of reliable preclinical models, development of new therapies has lagged behind. <p>We evaluated the efficacy of PhAc-ALGP-doxorubicin (ALGP-doxo), a prodrug metabolized to doxo by peptidases present in tumor cells and/or tumor microenvironment, in a synovial sarcoma (SynSa) and two dedifferentiated liposarcoma (DDLPS) patient-derived xenograft models...
May 31, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28550753/catalase-loaded-cisplatin-prodrug-constructed-liposomes-to-overcome-tumor-hypoxia-for-enhanced-chemo-radiotherapy-of-cancer
#7
Rui Zhang, Xuejiao Song, Chao Liang, Xuan Yi, Guosheng Song, Yu Chao, Yu Yang, Kai Yang, Liangzhu Feng, Zhuang Liu
Aiming at improved therapeutic efficacies, the combination of chemotherapy and radiotherapy (chemo-radiotherapy) has been widely studied and applied in clinic. However, the hostile characteristics of tumor microenvironment such as hypoxia often limit the efficacies in both types of cancer therapies. Herein, catalase (CAT), an antioxidant enzyme, is encapsulated inside liposomes constituted by cisplatin (IV)-prodrug-conjugated phospholipid, forming CAT@Pt (IV)-liposome for enhanced chemo-radiotherapy of cancer...
September 2017: Biomaterials
https://www.readbyqxmd.com/read/28522586/antitumor-synergism-and-enhanced-survival-with-a-tumor-vasculature-targeted-enzyme-prodrug-system-rapamycin-and-cyclophosphamide
#8
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
#9
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...
June 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28457884/substrate-mediated-enzyme-prodrug-therapy
#10
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
#11
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
#12
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
#13
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 prodrugs into drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on 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
#14
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...
May 26, 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
#15
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
#16
Chengyuan Zhang, Dayi Pan, Jin Li, Jiani Hu, Ashika Bains, Nicholas Guys, Hongyan Zhu, Xiaohui Li, Kui Luo, Qiyong Gong, Zhongwei Gu
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 glycyl phenylalanyl leucyl glycine 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 2, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28257943/photodynamic-therapy-enhances-the-efficacy-of-gene-directed-enzyme-prodrug-therapy
#17
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...
June 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/28164519/angiotensin-converting-enzyme-inhibitors-influence-on-antiplatelet-therapy-of-clopidogrel-in-acs
#18
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
#19
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
#20
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
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