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nitroreductase cancer

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https://www.readbyqxmd.com/read/29189173/prodrugs-for-nitroreductase-based-cancer-therapy-1-metabolite-profile-cell-cytotoxicity-and-molecular-modeling-interactions-of-nitro-benzamides-with-ssap-ntrb
#1
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
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
#2
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/28792090/distinct-activation-mechanisms-trigger-the-trypanocidal-activity-of-dna-damaging-prodrugs
#3
Emma Louise Meredith, Ambika Kumar, Aya Konno, Joanna Szular, Sam Alsford, Karin Seifert, David Horn, Shane R Wilkinson
Quinone-based compounds have been exploited to treat infectious diseases and cancer, with such chemicals often functioning as inhibitors of key metabolic pathways or as prodrugs. Here, we screened an aziridinyl 1,4-benzoquinone (ABQ) library against the causative agents of trypanosomiasis, and cutaneous leishmaniasis, identifying several potent structures that exhibited EC50 values of <100 nM. However, these compounds also displayed significant toxicity towards mammalian cells indicating that they are not suitable therapies for systemic infections...
October 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28741347/a-probe-for-the-detection-of-hypoxic-cancer-cells
#4
Shenzheng Luo, Rongfeng Zou, Junchen Wu, Markita P Landry
Hypoxia is a common feature of tumor cells. Nitroreductase (NTR), a common biomarker of hypoxia, has been widely used to evaluate the extent of tumor hypoxia. In this study, three fluorescent probes (FBN-1-3) were synthesized to monitor the extent of hypoxia in cancer cells in real time. FBN-1-3 were composed of a fluorescein analogue and one of three different aromatic nitro groups. Of these probes, FBN-1 showed excellent sensitivity and selectivity in detecting hypoxia via a reduction in O2 concentration...
August 25, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28475190/a-novel-off-on-fluorescent-probe-for-sensitive-imaging-of-mitochondria-specific-nitroreductase-activity-in-living-tumor-cells
#5
Bo Huang, Wen Chen, Yong-Qing Kuang, Wei Liu, Xian-Jun Liu, Li-Juan Tang, Jian-Hui Jiang
Sensitive and selective detection and imaging of nitroreductase (NTR) in cancer cells is of great importance for better understanding their biological functions. Since there are a few fluorescent probes concerning NTR activity specifically located in mitochondria, we developed a novel fluorescent benzoindocyanine probe (BICP) for mitochondrial NTR activity monitoring and imaging via extending a benzoindole moiety into a benzoindocyanine based fluorophore (BICF) with a strong intramolecular charge transfer (ICT) effect and incorporating 4-nitrobenzyl as a fluorescence-quenching and enzyme-responsive moiety...
May 28, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28262557/engineering-a-multifunctional-nitroreductase-for-improved-activation-of-prodrugs-and-pet-probes-for-cancer-gene-therapy
#6
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/27871834/ph-sensitive-pegylated-liposomes-for-delivery-of-an-acidic-dinitrobenzamide-mustard-prodrug-pathways-of-internalization-cellular-trafficking-and-cytotoxicity-to-cancer-cells
#7
COMPARATIVE STUDY
Mimi M Yang, William R Wilson, Zimei Wu
This paper aims to develop and evaluate a pH-sensitive PEGylated liposomal (pPSL) system for tumor-targeted intracellular delivery of SN25860, a weakly acidic, poorly water-soluble dinitrobenzamide mustard prodrug which is activated by the E. coli nitroreductase nfB. pPSL and non pH-sensitive liposomes (nPSL), as reference, were formulated by thin-film hydration; an active drug loading method was developed with the aid of solubilizers. Cytotoxicity was evaluated in an nfsB-transfected EMT6 mouse mammary carcinoma cell line...
January 10, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/27706901/targeting-a-targeted-drug-an-approach-toward-hypoxia-activatable-tyrosine-kinase-inhibitor-prodrugs
#8
Claudia Karnthaler-Benbakka, Diana Groza, Bettina Koblmüller, Alessio Terenzi, Katharina Holste, Melanie Haider, Dina Baier, Walter Berger, Petra Heffeter, Christian R Kowol, Bernhard K Keppler
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2-nitroimidazole-based hypoxia-activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture...
October 5, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27453434/rational-design-of-an-akr1c3-resistant-analog-of-pr-104-for-enzyme-prodrug-therapy
#9
Alexandra M Mowday, Amir Ashoorzadeh, Elsie M Williams, Janine N Copp, Shevan Silva, Matthew R Bull, Maria R Abbattista, Robert F Anderson, Jack U Flanagan, Christopher P Guise, David F Ackerley, Jeff B Smaill, Adam V Patterson
The clinical stage anti-cancer agent PR-104 has potential utility as a cytotoxic prodrug for exogenous bacterial nitroreductases expressed from replicating vector platforms. However substrate selectivity is compromised due to metabolism by the human one- and two-electron oxidoreductases cytochrome P450 oxidoreductase (POR) and aldo-keto reductase 1C3 (AKR1C3). Using rational drug design we developed a novel mono-nitro analog of PR-104A that is essentially free of this off-target activity in vitro and in vivo...
September 15, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27424910/theranostic-imaging-of-cancer-gene-therapy
#10
Thillai V Sekar, Ramasamy Paulmurugan
Gene-directed enzyme prodrug therapy (GDEPT) is a promising therapeutic approach for treating cancers of various phenotypes. This strategy is independent of various other chemotherapeutic drugs used for treating cancers where the drugs are mainly designed to target endogenous cellular mechanisms, which are different in various cancer subtypes. In GDEPT an external enzyme, which is different from the cellular proteins, is expressed to convert the injected prodrug in to a toxic metabolite, that normally kill cancer cells express this protein...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/26794346/hydrolysed-inulin-alleviates-the-azoxymethane-induced-preneoplastic-aberrant-crypt-foci-by-altering-selected-intestinal-microbiota-in-sprague-dawley-rats
#11
Thanawat Pattananandecha, Sasithorn Sirilun, Yodsawee Duangjitcharoen, Bhagavathi Sundaram Sivamaruthi, Prasit Suwannalert, Sartjin Peerajan, Chaiyavat Chaiyasut
Context Inulin, a non-digestible carbohydrate isolated from Helianthus tuberosus L. (Asteraceae), has been shown to alter the gut beneficial bacteria including Lactobacillus spp. and Bifidobacteria. Inulin also influences the activities of intestinal microbiota that could prevent the colon cancer development. Objective This study determines the effect of hydrolysed inulin with different degrees of polymerisation on alteration of intestinal microbiota and their activities on azoxymethane (AOM)-induced preneoplastic aberrant crypt foci (ACF) in rats...
September 2016: Pharmaceutical Biology
https://www.readbyqxmd.com/read/26415543/identification-of-novel-nitroreductases-from-bacillus-cereus-and-their-interaction-with-the-cb1954-prodrug
#12
Vanessa V Gwenin, Paramasivan Poornima, Jennifer Halliwell, Patrick Ball, George Robinson, Chris D Gwenin
Directed enzyme prodrug therapy is a form of cancer chemotherapy in which bacterial prodrug-activating enzymes, or their encoding genes, are directed to the tumour before administration of a prodrug. The prodrug can then be activated into a toxic drug at the tumour site, reducing off-target effects. The bacterial nitroreductases are a class of enzymes used in this therapeutic approach and although very promising, the low turnover rate of prodrug by the most studied nitroreductase enzyme, NfnB from Escherichia coli (NfnB_Ec), is a major limit to this technology...
December 1, 2015: Biochemical Pharmacology
https://www.readbyqxmd.com/read/26110789/development-of-a-bioluminescent-nitroreductase-probe-for-preclinical-imaging
#13
Anzhelika G Vorobyeva, Michael Stanton, Aurélien Godinat, Kjetil B Lund, Grigory G Karateev, Kevin P Francis, Elizabeth Allen, Juri G Gelovani, Emmet McCormack, Mark Tangney, Elena A Dubikovskaya
Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity...
2015: PloS One
https://www.readbyqxmd.com/read/25689597/unravelling-the-role-of-snm1-in-the-dna-repair-system-of-trypanosoma-brucei
#14
James A Sullivan, Jie Lun Tong, Martin Wong, Ambika Kumar, Hajrah Sarkar, Sarah Ali, Ikran Hussein, Iqra Zaman, Emma Louise Meredith, Nuala A Helsby, Longqin Hu, Shane R Wilkinson
All living cells are subject to agents that promote DNA damage. A particularly lethal lesion are interstrand cross-links (ICL), a property exploited by several anti-cancer chemotherapies. In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO2/SNM1 nucleases. Here, we report that Trypanosoma brucei, the causative agent of African trypanosomiasis, possesses a bona fide member of this family (called TbSNM1) with expression of the parasite enzyme able to suppress the sensitivity yeast pso2Δ mutants display towards mechlorethamine, an ICL-inducing compound...
May 2015: Molecular Microbiology
https://www.readbyqxmd.com/read/25584074/galacto-oligosaccharides-and-colorectal-cancer-feeding-our-intestinal-probiome
#15
Jose M Bruno-Barcena, M Andrea Azcarate-Peril
Prebiotics are ingredients selectively fermented by the intestinal microbiota that promote changes in the microbial community structure and/or their metabolism, conferring health benefits to the host. Studies show that β (1-4) galacto-oligosaccharides [β (1-4) GOS], lactulose and fructo-oligosaccharides increase intestinal concentration of lactate and short chain fatty acids, and stool frequency and weight, and they decrease fecal concentration of secondary bile acids, fecal pH, and nitroreductase and β-glucuronidase activities suggesting a clear role in colorectal cancer (CRC) prevention...
January 2015: Journal of Functional Foods
https://www.readbyqxmd.com/read/25575867/genetically-engineered-theranostic-mesenchymal-stem-cells-for-the-evaluation-of-the-anticancer-efficacy-of-enzyme-prodrug-systems
#16
Faranak Salman Nouri, Xing Wang, Arash Hatefi
Over the past decade, various enzyme/prodrug systems such as thymidine kinase/ganciclovir (TK/GCV), yeast cytosine deaminase/5-fluorocytosine (yCD/5-FC) and nitroreductase/CB1954 (NTR/CB1954) have been used for stem cell mediated suicide gene therapy of cancer. Yet, no study has been conducted to compare and demonstrate the advantages and disadvantages of using one system over another. Knowing that each enzyme/prodrug system has its own strengths and weaknesses, we utilized mesenchymal stem cells (MSCs) as a medium to perform for the first time a comparative study that illustrated the impact of subtle differences among these systems on the therapeutic outcome...
February 28, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/25338741/gene-directed-enzyme-prodrug-therapy
#17
REVIEW
Jin Zhang, Vijay Kale, Mingnan Chen
As one targeting strategy of prodrug delivery, gene-directed enzyme prodrug therapy (GDEPT) promises to realize the targeting through its three key features in cancer therapy-cell-specific gene delivery and expression, controlled conversion of prodrugs to drugs in target cells, and expanded toxicity to the target cells' neighbors through bystander effects. After over 20 years of development, multiple GDEPT systems have advanced into clinical trials. However, no GDEPT product is currently marketed as a drug, suggesting that there are still barriers to overcome before GDEPT becomes a standard therapy...
January 2015: AAPS Journal
https://www.readbyqxmd.com/read/25124221/site-directed-delivery-of-nitric-oxide-to-cancers
#18
REVIEW
Kavita Sharma, Harinath Chakrapani
Nitric oxide (NO) is a reactive gaseous free radical which mediates numerous biological processes. At elevated levels, NO is found to be toxic to cancers and hence, a number of strategies for site-directed delivery of NO to cancers are in development during the past two decades. More recently, the focus of research has been to, in conjunction with other cancer drugs deliver NO to cancers for its secondary effects including inhibition of cellular drug efflux pumps. Among the various approaches toward site-selective delivery of exogenous NO sources, enzyme activated nitric oxide donors belonging to the diazeniumdiolate category afford unique advantages including exquisite control of rates of NO generation and selectivity of NO production...
December 1, 2014: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/25031704/a-fiber-modified-adenovirus-co-expressing-hsv-tk-and-coli-ntr-enhances-antitumor-activities-in-breast-cancer-cells
#19
Yang Zhan, Bin Yu, Zhen Wang, Yu Zhang, Hai-Hong Zhang, Hao Wu, Xiao Feng, Ran-Shen Geng, Wei Kong, Xiang-Hui Yu
Breast cancers especially in late and metastatic stages remain refractory to treatment despite advances in surgical techniques and chemotherapy. Suicide gene therapy based on adenoviral technology will be promising strategies for such advanced diseases. We previously showed that co-expression of herpes simplex virus thymidine kinase (HSV-TK) and Escherichia coli nitroreductase (Coli.NTR) by an hTERT-driven adenovirus vector resulted in additive anti-tumor effects in breast cancer cells in vitro and in vivo...
2014: International Journal of Clinical and Experimental Pathology
https://www.readbyqxmd.com/read/24202330/the-flavin-reductase-msue-is-a-novel-nitroreductase-that-can-efficiently-activate-two-promising-next-generation-prodrugs-for-gene-directed-enzyme-prodrug-therapy
#20
Laura K Green, Mathew A Storey, Elsie M Williams, Adam V Patterson, Jeff B Smaill, Janine N Copp, David F Ackerley
Bacterial nitroreductase enzymes that can efficiently catalyse the oxygen-independent reduction of prodrugs originally developed to target tumour hypoxia offer great potential for expanding the therapeutic range of these molecules to aerobic tumour regions, via the emerging cancer strategy of gene-directed enzyme prodrug therapy (GDEPT). Two promising hypoxia prodrugs for GDEPT are the dinitrobenzamide mustard PR-104A, and the nitrochloromethylbenzindoline prodrug nitro-CBI-DEI. We describe here use of a nitro-quenched fluorogenic probe to identify MsuE from Pseudomonas aeruginosa as a novel nitroreductase candidate for GDEPT...
2013: Cancers
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