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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/29147875/evaluation-of-nfsa-like-nitroreductases-from-neisseria-meningitidis-and-bartonella-henselae-for-enzyme-prodrug-therapy-targeted-cellular-ablation-and-dinitrotoluene-bioremediation
#1
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
https://www.readbyqxmd.com/read/29131143/nonimmune-cells-equipped-with-t-cell-receptor-like-signaling-for-cancer-cell-ablation
#2
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...
November 13, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/29119917/use-of-e-coli-purine-nucleoside-phosphorylase-in-the-treatment-of-solid-tumors
#3
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
https://www.readbyqxmd.com/read/29090347/hepatic-intra-arterial-delivery-of-a-trojan-horses-gene-therapy-a-pilot-study-on-rabbit-vx2-hepatic-tumor-model
#4
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...
October 31, 2017: Cardiovascular and Interventional Radiology
https://www.readbyqxmd.com/read/29057403/fluorogenic-reaction-based-prodrug-conjugates-as-targeted-cancer-theranostics
#5
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...
October 23, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/29054356/enzyme-prodrug-therapies-and-therapeutic-enzymes
#6
EDITORIAL
Brigitte Städler, Alexander N Zelikin
No abstract text is available yet for this article.
October 17, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-from-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistance
#7
REVIEW
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
https://www.readbyqxmd.com/read/28916498/antibody-directed-enzyme-prodrug-therapy-adept-trials-and-tribulations
#8
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
https://www.readbyqxmd.com/read/28916497/two-step-polymer-and-liposome-enzyme-prodrug-therapies-for-cancer-pdept-and-pelt-concepts-and-future-perspectives
#9
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
https://www.readbyqxmd.com/read/28916496/designer-bacteria-as-intratumoural-enzyme-biofactories
#10
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
https://www.readbyqxmd.com/read/28916493/cell-mediated-enzyme-prodrug-cancer-therapies
#11
Rachael Mooney, Asma Abdul Majid, Jennifer Batalla, Alexander J Annala, Karen S Aboody
Cell-directed gene therapy is a promising new frontier for the field of targeted cancer therapies. Here we discuss the current pre-clinical and clinical use of cell-mediated enzyme prodrug therapy (EPT) directed against solid tumors and avenues for further development. We also discuss some of the challenges encountered upon translating these therapies to clinical trials. Upon sufficient development, cell-mediated enzyme prodrug therapy has the potential to maximize the distribution of therapeutic enzymes within the tumor environment, localizing conversion of prodrug to active drug at the tumor sites thereby decreasing off-target toxicities...
September 13, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28912080/induced-prodrug-activation-by-conditional-protein-degradation
#12
Andrew S Gaynor, Wilfred Chen
Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation-Directed Enzyme Prodrug Therapy (DDEPT)...
September 11, 2017: Journal of Biotechnology
https://www.readbyqxmd.com/read/28859899/combination-of-using-prodrug-modified-cationic-liposome-nanocomplexes-and-a-potentiating-strategy-via-targeted-co-delivery-of-gemcitabine-and-docetaxel-for-cd44-overexpressed-triple-negative-breast-cancer-therapy
#13
Yang Fan, Qingjie Wang, Guimei Lin, Yanbin Shi, Zili Gu, Tingting Ding
In this study, novel prodrug-modified cationic liposome nanocomplexes (Combo NCs) were reported for gemcitabine (GEM) and docetaxel (DTX) co-delivery. This nanoplatform exhibited multiple favorable characteristics, such as a 'green' fabrication with a one-step chemical reaction, appropriate size (∼200nm) and distribution (PDI<0.2), low zeta potential (-31.1mv), high drug-loading efficiency (9.3% GEM plus 3.1% DTX, wt%) and pH and enzymatic dual-stimulus-responsive release properties. Immunofluorescence and cellular uptake studies showed that Combo NCs efficiently targeted overexpressed CD44 in MDA-MB-231 carcinoma...
August 30, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28838843/targeted-antitumor-therapy-mediated-by-prodrug-activating-mesenchymal-stromal-cells
#14
REVIEW
Lucia Kucerova, Erika Durinikova, Lenka Toro, Marina Cihova, Svetlana Miklikova, Martina Poturnajova, Zuzana Kozovska, Miroslava Matuskova
Mesenchymal stromal cells (MSCs) were introduced as tumor-targeted vehicles suitable for delivery of the gene-directed enzyme/prodrug therapy more than 10 years ago. Over these years key properties of tumor cells and MSCs, which are crucial for the treatment efficiency, were examined; and there are some critical issues to be considered for the maximum antitumor effect. Moreover, engineered MSCs expressing enzymes capable of activating non-toxic prodrugs achieved long-term curative effect even in metastatic and hard-to-treat tumor types in pre-clinical scenario(s)...
November 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28827774/mepicides-potent-antimalarial-prodrugs-targeting-isoprenoid-biosynthesis
#15
Rachel L Edwards, Robert C Brothers, Xu Wang, Maxim I Maron, Peter D Ziniel, Patricia S Tsang, Thomas E Kraft, Paul W Hruz, Kim C Williamson, Cynthia S Dowd, Audrey R Odom John
The emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28796151/potential-development-of-tumor-targeted-oral-anti-cancer-prodrugs-amino-acid-and-dipeptide-monoester-prodrugs-of-gemcitabine
#16
Yasuhiro Tsume, Adam J Drelich, David E Smith, Gordon L Amidon
One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine...
August 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28752801/virus-directed-enzyme-prodrug-therapy-and-the-assessment-of-the-cytotoxic-impact-of-some-benzimidazole-derivatives
#17
Michał Szewczuk, Karolina Boguszewska, Marta Żebrowska, Ewa Balcerczak, Marta Stasiak, Maria Świątkowska, Katarzyna Błaszczak-Świątkiewicz
Virus-directed enzyme prodrug therapy is one of the major strategy of increasing cytotoxicity of bioreductive agents. This research intended to examine new selected benzimidazole derivatives as a substrate for nitroreductase, the enzyme involved in nitroreduction which is responsible to the production of cytotoxic metabolites. In this way, the selectivity and strength of cytotoxicity can be raised. The effect of benzimidazoles on virus transfected cells and non-virus transfected cells A549 cell line was established by Annexin V + propidium iodide test, western blot, and polymerase chain reaction analysis of specific pro- and anti-apoptotic proteins in the corresponding gene expression and additionally nitroreductase gene expression...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28748212/genetically-engineered-multilineage-differentiating-stress-enduring-cells-as-cellular-vehicles-against-malignant-gliomas
#18
Tomohiro Yamasaki, Shohei Wakao, Hiroshi Kawaji, Shinichiro Koizumi, Tetsuro Sameshima, Mari Dezawa, Hiroki Namba
Malignant glioma, the most common malignant brain tumor in adults, is difficult to treat due to its aggressive invasive nature. Enzyme/prodrug suicide gene therapy based on the herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) system is an efficient strategy for treating malignant gliomas. In the present study, we evaluated treatment with multilineage-differentiating stress-enduring (Muse) cells, which are endogenous non-tumorigenic pluripotent-like stem cells that are easily collectable from the bone marrow as SSEA-3(+) cells, as carriers of the HSVtk gene...
September 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/28741467/status-quo-in-antibody-drug-conjugates-can-glyco-enzymes-solve-the-current-challenges
#19
Florentina Kubizek, Britta Eggenreich, Oliver Spadiut
Over the last years, a novel class of anti-cancer drugs named antibody-drug conjugates (ADCs) has been developed. Due to their limited off-target toxicity but highly potent cytotoxicity at tumor sites, ADCs have proven to be a good alternative to ordinary cancer treatment, such as chemotherapy or combination therapy. Numerous enhancements in antibody-drug engineering led to highly potent tumor targeting drugs with a wide therapeutic window. Two ADCs (Brentuximab vedotin and Trastuzumab emtansine) are already on the market and many others in clinical trials...
July 24, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28727740/genetically-engineered-suicide-gene-in-mesenchymal-stem-cells-using-a-tet-on-system-for-anaplastic-thyroid-cancer
#20
Senthilkumar Kalimuthu, Ji Min Oh, Prakash Gangadaran, Liya Zhu, Ho Won Lee, Yong Hyun Jeon, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Anaplastic thyroid cancer (ATC) is the most aggressive malignancy of the thyroid, during which undifferentiated tumors arise from the thyroid follicular epithelium. ATC has a very poor prognosis due to its aggressive behavior and poor response to conventional therapies. Gene-directed enzyme/prodrug therapy using genetically engineered mesenchymal stromal cells (MSC) is a promising therapeutic strategy. The doxycycline (DOX)-controlled Tet inducible system is the most widely utilized regulatory system and could be a useful tool for therapeutic gene-based therapies...
2017: PloS One
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