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enzyme prodrug therapy

Xizhen Lian, Yanyan Huang, Yuanyuan Zhu, Yu Fang, Rui Zhao, Elizabeth Joseph, Jialuo Li, Jean-Phillipe Pellois, Hongcai Zhou
Prodrug activation by exogenously administered enzymes for cancer therapy is an approach to achieve better selectivity and less systemic toxicity than conventional chemotherapy. However, the short half-lives of the activating enzymes in bloodstream has limited its success. Here, we demonstrate that a tyrosinase-MOF nanoreactor activates the prodrug paracetamol in cancer cells in a long-lasting manner. By generating reactive oxygen species (ROS) and depleting glutathione (GSH), the product of enzymatic conversion of paracetamol is toxic to drug-resistant cancer cells...
March 13, 2018: Angewandte Chemie
Raquel T Yokoda, Bolni M Nagalo, Mitesh J Borad
Gastrointestinal malignancies are challenging cancers with considerable economic and societal impacts on health care systems worldwide. While advances in surgical approaches have provided benefits to a proportion of patients, only modest improvements have been attained in the treatment of patients with advanced disease, resulting in limited improvement in survival rates in these patients. Oncolytic adenoviruses are being developed to address gastrointestinal malignancies. Each platform has evolved to maximize tumor-cell killing potency while minimizing toxicities...
March 11, 2018: Biomedicines
Daniel Elbaum, Maria G Beconi, Edith Monteagudo, Annalise Di Marco, Maria S Quinton, Kathryn A Lyons, Andrew Vaino, Steven Harper
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients...
2018: PloS One
Gregor Fuhrmann, Rona Chandrawati, Paresh A Parmar, Timothy J Keane, Stephanie A Maynard, Sergio Bertazzo, Molly M Stevens
Extracellular vesicles (EVs) have recently gained significant attention as important mediators of intercellular communication, potential drug carriers, and disease biomarkers. These natural cell-derived nanoparticles are postulated to be biocompatible, stable under physiological conditions, and to show reduced immunogenicity as compared to other synthetic nanoparticles. Although initial clinical trials are ongoing, the use of EVs for therapeutic applications may be limited due to undesired off-target activity and potential "dilution effects" upon systemic administration which may affect their ability to reach their target tissues...
February 23, 2018: Advanced Materials
Kanchan Chauhan, Juan M Hernandez-Meza, Ana G Rodríguez-Hernández, Karla Juarez-Moreno, Prakhar Sengar, Rafael Vazquez-Duhalt
BACKGROUND: Tamoxifen is the standard endocrine therapy for breast cancers, which require metabolic activation by cytochrome P450 enzymes (CYP). However, the lower and variable concentrations of CYP activity at the tumor remain major bottlenecks for the efficient treatment, causing severe side-effects. Combination nanotherapy has gained much recent attention for cancer treatment as it reduces the drug-associated toxicity without affecting the therapeutic response. RESULTS: Here we show the modular design of P22 bacteriophage virus-like particles for nanoscale integration of virus-driven enzyme prodrug therapy and photodynamic therapy...
February 20, 2018: Journal of Nanobiotechnology
S V Kalinichenko, M V Shepelev, P N Vikhreva, I V Korobko
describe a novel hybrid tumor-specific promoter, ARE-hTERT, composed of the human TERT gene promoter (hTERT) and the antioxidant response element (ARE) from the human GCLM gene promoter. The hybrid promoter retains the tumor specificity of the basal hTERT promoter but is characterized by an enhanced transcriptional activity in cancer cells with abnormal activation of the Nrf2 transcription factor and upon induction of oxidative stress. In the in vitro enzyme-prodrug cancer gene therapy scheme, ARE-hTERT promoter-driven expression of CD : UPRT (yeast cytosine deaminase : uracil phosphoribosyltransferase) chimeric protein induced a more pronounced death of cancer cells either upon treatment with 5-fluorouracil (5FC) alone or when 5FC was combined with chemotherapeutic drugs as compared to the hTERT promoter...
October 2017: Acta Naturae
Fatma Haddad, Maryam Sawalha, Yahya Khawaja, Anas Najjar, Rafik Karaman
Background : Parkinson's disease is an aggressive and progressive neurodegenerative disorder that depletes dopamine (DA) in the central nervous system. Dopamine replacement therapy, mainly through actual dopamine and its original prodrug l-dopa (LD), faces many challenges such as poor blood brain barrier penetration and decreased response to therapy with time. Methods : The prodrugs described herein are ester, amide, dimeric amide, carrier-mediated, peptide transport-mediated, cyclic, chemical delivery systems and enzyme-models prodrugs designed and made by chemical means, and their bioavailability was studied in animals...
December 25, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Praveen Reddy Adiyala, Venkatesh Tekumalla, Ibrahim Bin Sayeed, V Lakshma Nayak, Apoorva Nagarajan, Mohd Adil Shareef, Burri Nagaraju, Ahmed Kamal
Cancer chemotherapy has several limitations such as often insufficient differentiation between malign tissue and benign tissue. The clinical utility of the pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are inadequate because of the lack of selectivity for tumor tissues, high reactivity of the pharmacophoric imine functionality, low water solubility, and stability. To address these limitations two new β-glucoside prodrugs of PBDs have been synthesized and evaluated for their potential use in selective therapy of solid tumors by ADEPT...
February 2018: Bioorganic Chemistry
Tugba Gungor, Gulden Yetis, Ferah Cömert Onder, Esra Tokay, Tugba Taşkın Tok, Ayhan Celik, Mehmet Ay, Feray Kockar
BACKGROUND: Directed Enzyme Prodrug Therapy (DEPT) as an alternative method against conventional cancer treatments, in which the non-toxic prodrug is converted to highly cytotoxic derivative, has attracted an ample attentions in recent years for cancer therapy studies. OBJECTIVE: The metabolite profile, cell cytotoxicity and molecular modeling interactions of a series of nitro benzamides with Ssap-NtrB were investigated in this study. METHOD: A series of nitro-substituted benzamide prodrugs (1-4) were synthesized and firstly investigated their enzymatic reduction by Ssap-NtrB (S...
November 29, 2017: Medicinal Chemistry
Amit Sharma, Eun-Joong Kim, Hu Shi, Jin Yong Lee, Bong Geun Chung, Jong Seung Kim
The high incidence of colorectal cancer worldwide is currently a major health concern. Although conventional chemotherapy and surgery are effective to some extent, there is always a risk of relapse due to associated side effects, including post-surgical complications and non-discrimination between cancer and normal cells. In this study, we developed a small molecule-based theranostic system, Gal-Dox, which is preferentially taken up by colon cancer cells through receptor-mediated endocytosis. After cancer-specific activation, the active drug Dox (doxorubicin) is released with a fluorescence turn-on response, allowing both drug localization and site of action to be monitored...
February 2018: Biomaterials
Michelle H Rich, Abigail V Sharrock, Kelsi R Hall, David F Ackerley, Joanna K MacKichan
OBJECTIVES: To characterize the activities of two candidate nitroreductases, Neisseria meningitidis NfsA (NfsA_Nm) and Bartonella henselae (PnbA_Bh), with the nitro-prodrugs, CB1954 and metronidazole, and the environmental pollutants 2,4- and 2,6-dinitrotoluene. RESULTS: NfsA_Nm and PnbA_Bh were evaluated in Escherichia coli over-expression assays and as His6-tagged proteins in vitro. With the anti-cancer prodrug CB1954, both enzymes were more effective than the canonical O2-insensitive nitroreductase E...
November 17, 2017: Biotechnology Letters
Ryosuke Kojima, Leo Scheller, Martin Fussenegger
The ability to engineer custom cell-contact-sensing output devices into human nonimmune cells would be useful for extending the applicability of cell-based cancer therapies and for avoiding risks associated with engineered immune cells. Here we have developed a new class of synthetic T-cell receptor-like signal-transduction device that functions efficiently in human nonimmune cells and triggers release of output molecules specifically upon sensing contact with a target cell. This device employs an interleukin signaling cascade, whose OFF/ON switching is controlled by biophysical segregation of a transmembrane signal-inhibitory protein from the sensor cell-target cell interface...
January 2018: Nature Chemical Biology
William B Parker, Eric J Sorscher
BACKGROUND: The selective expression of non-human genes in tumor tissue to activate non-toxic compounds (Gene Directed Prodrug Enzyme Therapy, GDEPT) is a novel strategy designed for killing tumor cells in patients with little or no systemic toxicity. Numerous non-human genes have been evaluated, but none have yet been successful in the clinic. METHODS: Unlike human purine nucleoside phosphorylase (PNP), E. coli PNP accepts adenine containing nucleosides as substrates, and is therefore able to selectively activate non-toxic purine analogs in tumor tissue...
November 8, 2017: Current Pharmaceutical Design
Olivier Pellerin, Ikram Amara, Marc Sapoval, Tchao Méachi, Carole Déan, Philippe Beaune, Isabelle de Waziers
PURPOSE: Gene-directed enzyme prodrug therapy (GDEPT) is a "Trojan-horses" suicide gene therapy that consists of tumor-targeted gene delivery (vectorized by mesenchymal stem cells MSCs) encoding an enzyme that converts a harmless prodrug into cytotoxic metabolites in situ. Then, cytotoxic metabolites passively diffuse in the neighboring tumor cells and kill them (bystander effect). The goal of our study was to assess the feasibility and efficacy of intra-arterial administration of MSCs transduced with an optimized gene (MSC-CYP2B6TM-RED) followed by intravenous administration of cyclophosphamide (CPA) into the VX2 rabbit liver tumor...
January 2018: Cardiovascular and Interventional Radiology
Min Hee Lee, Amit Sharma, Min Jung Chang, Jinju Lee, Subin Son, Jonathan L Sessler, Chulhun Kang, Jong Seung Kim
Theranostic systems are receiving ever-increasing attention due to their potential therapeutic utility, imaging enhancement capability, and promise for advancing the field of personalized medicine, particularly as it relates to the diagnosis, staging, and treatment of cancer. In this Tutorial Review, we provide an introduction to the concepts of theranostic drug delivery effected via use of conjugates that are able to target cancer cells selectively, provide cytotoxic chemotherapeutics, and produce readily monitored imaging signals in vitro and in vivo...
January 2, 2018: Chemical Society Reviews
Brigitte Städler, Alexander N Zelikin
No abstract text is available yet for this article.
October 17, 2017: Advanced Drug Delivery Reviews
Julie Laborde, Céline Deraeve, Vania Bernardes-Génisson
The place of prodrugs in the current antitubercular therapeutic arsenal is preponderant, since two of the four first-line antitubercular agents, isoniazid (INH) and pyrazinamide (PZA), need to be activated by Mycobacterium tuberculosis before exerting their activity. In addition, six other prodrugs can be found in the second- and third-line therapeutic regimens. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy. In the case of prodrugs, the resistance phenomenon is often related to a mutation in the gene encoding for the activation enzymes, resulting thus in a default of these enzymes that are no more able to activate prodrugs...
October 20, 2017: ChemMedChem
Surinder K Sharma, Kenneth D Bagshawe
Antibody directed enzyme prodrug therapy has the potential to be an effective therapy for most common solid cancers. Clinical studies with CPG2 system have shown the feasibility of this approach. The key limitation has been immunogenicity of the enzyme. Technologies now exist to eliminate this problem. Non-immunogenic enzymes in combination with prodrugs that generate potent cytotoxic drugs can provide a powerful approach to cancer therapy. ADEPT has the potential to be non -toxic to normal tissue and can therefore be combined with other modalities including immunotherapy for greater clinical benefit...
September 12, 2017: Advanced Drug Delivery Reviews
Anna Scomparin, Helena F Florindo, Galia Tiram, Elaine L Ferguson, Ronit Satchi-Fainaro
Polymer-directed enzyme prodrug therapy (PDEPT) and polymer enzyme liposome therapy (PELT) are two-step therapies developed to provide anticancer drugs site-selective intratumoral accumulation and release. Nanomedicines, such as polymer-drug conjugates and liposomal drugs, accumulate in the tumor site due to extravasation-dependent mechanism (enhanced permeability and retention - EPR - effect), and further need to cross the cellular membrane and release their payload in the intracellular compartment. The subsequent administration of a polymer-enzyme conjugate able to accumulate in the tumor tissue and to trigger the extracellular release of the active drug showed promising preclinical results...
September 12, 2017: Advanced Drug Delivery Reviews
Panos Lehouritis, Glenn Hogan, Mark Tangney
Bacterial-directed enzyme prodrug therapy (BDEPT) is an emerging form of treatment for cancer. It is a biphasic variant of gene therapy in which a bacterium, armed with an enzyme that can convert an inert prodrug into a cytotoxic compound, induces tumour cell death following tumour-specific prodrug activation. BDEPT combines the innate ability of bacteria to selectively proliferate in tumours, with the capacity of prodrugs to undergo contained, compartmentalised conversion into active metabolites in vivo. Although BDEPT has undergone clinical testing, it has received limited clinical exposure, and has yet to achieve regulatory approval...
September 12, 2017: Advanced Drug Delivery Reviews
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