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enzyme prodrug therapy

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https://www.readbyqxmd.com/read/28921911/update-of-antitubercular-prodrugs-in-a-molecular-perspective-mechanisms-of-action-bioactivation-pathways-and-associated-resistances
#1
Vania Bernardes Genisson, Julie Laborde, Céline Deraeve
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, namely ethionamide (ETH), prothionamide (PTH), p-aminosalicylic acid (PAS), thiacetazone (TAC), isoxyl (ISO) and the recently approved delamanid. The emergence of mycobacterial strains resistant to one or several antitubercular agents is one of the main issues of the antitubercular therapy...
September 16, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28916498/antibody-directed-enzyme-prodrug-therapy-adept-trials-and-tribulations
#2
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
#3
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
#4
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
#5
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 12, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28912080/induced-prodrug-activation-by-conditional-protein-degradation
#6
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
#7
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 (∼ 200 nm) and distribution (PDI < 0.2), low zeta potential (-31.1 mv), 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 28, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28838843/targeted-antitumor-therapy-mediated-by-prodrug-activating-mesenchymal-stromal-cells
#8
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)...
August 25, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28827774/mepicides-potent-antimalarial-prodrugs-targeting-isoprenoid-biosynthesis
#9
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
#10
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
#11
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
#12
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
#13
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
#14
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
https://www.readbyqxmd.com/read/28714209/biotransporting-self-assembled-nanofactories-using-polymer-vesicles-with-molecular-permeability-for-enzyme-prodrug-cancer-therapy
#15
Tomoki Nishimura, Yoshihiro Sasaki, Kazunari Akiyoshi
As "biotransporting nanofactories", in vivo therapeutic biocatalyst nanoreactors would enable encapsulated enzymes to transform inert prodrugs or neutralize toxic compounds at target disease sites. This would offer outstanding potential for next-generation therapeutic platforms, such as enzyme prodrug therapy. Designing such advanced materials has, however, proven challenging. Here, it is shown that self-assembled nanofactories formulate with polymeric vesicles with an intrinsically permeable membrane. The vesicles, CAPsomes, are composed of carbohydrate-b-poly(propylene glycol) and show molecular-weight-depended permeability...
July 17, 2017: Advanced Materials
https://www.readbyqxmd.com/read/28703313/mesenchymal-stem-cells-a-new-platform-for-targeting-suicide-genes-in-cancer
#16
REVIEW
Rana Moradian Tehrani, Javad Verdi, Mahdi Noureddini, Rasoul Salehi, Reza Salarinia, Meysam Mosalaei, Miganosh Simonian, Behrang Alani, Moosa Rahimi Ghiasi, Mahmoud Reza Jaafari, Hamid Reza Mirzaei, Hamed Mirzaie
One of the important strategies for the treatment of cancer is gene therapy which has the potential to exclusively eradicate malignant cells, without any damage to the normal tissues. Gene-directed enzyme prodrug therapy (GDEPT) is a two-step gene therapy approach, where a suicide gene is directed to tumor cells. The gene encodes an enzyme that expressed intracellularly where it is able to convert a prodrug into cytotoxic metabolites. Various delivery systems have been developed to achieve the appropriate levels of tumor restricted expression of chemotherapeutic drugs...
July 13, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28699219/enzyme-prodrug-therapy-engineered-into-electrospun-fibers-with-embedded-liposomes-for-controlled-localized-synthesis-of-therapeutics
#17
Rona Chandrawati, Morten T J Olesen, Thatiane C C Marini, Gurpal Bisra, Anne Géraldine Guex, Marcelo G de Oliveira, Alexander N Zelikin, Molly M Stevens
Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β-glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β-glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks...
September 2017: Advanced Healthcare Materials
https://www.readbyqxmd.com/read/28684168/rnai-prodrugs-targeting-plk1-induce-specific-gene-silencing-in-primary-cells-from-pediatric-t-acute-lymphoblastic-leukemia-patients
#18
Iryna Kolosenko, Elin Edsbäcker, Ann-Charlotte Björklund, Alexander S Hamil, Oksana Goroshchuk, Dan Grandér, Steven F Dowdy, Caroline Palm-Apergi
Epidemiological studies of childhood leukemia survivors reveal an alarmingly high incidence of chronic health disabilities after treatment, therefore, more specific therapies need to be developed. Polo-like kinase 1 (Plk1) is a key player in mitosis and a target for drug development as it is upregulated in multiple cancer types. Small molecules targeting Plk1 are mainly ATP-competitors and, therefore, are known to elicit side effects due to lack of specificity. RNA interference (RNAi) is known for its high catalytic activity and target selectivity; however, the biggest barrier for its introduction into clinical use is its delivery...
September 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28676386/prodrugs-in-medicinal-chemistry-and-enzyme-prodrug-therapies
#19
Raoul Walther, Jarkko Rautio, Alexander N Zelikin
Prodrugs are cunning derivatives of therapeutic agents designed to improve the pharmacokinetics profile of the drug. Within a prodrug, pharmacological activity of the drug is masked and is recovered within the human body upon bioconversion of the prodrug, a process that is typically mediated by enzymes. This concept is highly successful and a significant fraction of marketed therapeutic formulations is based on prodrugs. An advanced subset of prodrugs can be engineered such as to achieve site-specific bioconversion of the prodrug - to comprise the highly advantageous "enzyme prodrug therapy", EPT...
July 1, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28675414/nanotekniken-kan-revolutionera-behandlingen-av-cancer-ger-nya-m%C3%A3-jligheter-att-m%C3%A3-lstyra-l%C3%A3-kemedel-men-flera-stora-utmaningar-%C3%A3-terst%C3%A3-r-att-tackla
#20
Matthias Löhr, Wouter van der Wijngaart, Björn Fagerberg
Nanoparticles for cancer therapy Nanoparticles carry a big promise in oncology, for diagnosis/imaging, therapy, or both (theragnostics). As common in medical history, there is a huge gap between the exciting experimental possibilities and data and clinical studies making use of it. Of the cell-containing nanoparticles, only one formulation using gene-directed enzyme prodrug therapy (GDEPT) with CYP2B1 and ifosfamide was used in early clinical studies. Of the cell-free nanoparticles, some drug-releasing (doxorubicin) ones are in clinical use for trans-arterial chemo-embolization (TACE) in liver tumors and metastasis...
July 3, 2017: Läkartidningen
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