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排序方式: 共有540条查询结果,搜索用时 31 毫秒
1.
Erik W. Martin Marguerite S. Buzza Kathryn H. Driesbaugh Shihui Liu Yolanda M. Fortenberry Stephen H. Leppla Toni M. Antalis 《Oncotarget》2015,6(32):33534-33553
The membrane-anchored serine proteases are a unique group of trypsin-like serine proteases that are tethered to the cell surface via transmembrane domains or glycosyl-phosphatidylinositol-anchors. Overexpressed in tumors, with pro-tumorigenic properties, they are attractive targets for protease-activated prodrug-like anti-tumor therapies. Here, we sought to engineer anthrax toxin protective antigen (PrAg), which is proteolytically activated on the cell surface by the proprotein convertase furin to instead be activated by tumor cell-expressed membrane-anchored serine proteases to function as a tumoricidal agent. PrAg''s native activation sequence was mutated to a sequence derived from protein C inhibitor (PCI) that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS. PrAg-PCIS was resistant to furin cleavage in vitro, yet cytotoxic to multiple human tumor cell lines when combined with FP59, a chimeric anthrax toxin lethal factor-Pseudomonas exotoxin fusion protein. Molecular analyses showed that PrAg-PCIS can be cleaved in vitro by several serine proteases including the membrane-anchored serine protease testisin, and mediates increased killing of testisin-expressing tumor cells. Treatment with PrAg-PCIS also potently attenuated the growth of testisin-expressing xenograft tumors in mice. The data indicates PrAg can be engineered to target tumor cell-expressed membrane-anchored serine proteases to function as a potent tumoricidal agent. 相似文献
2.
Synthesis and Evaluation of a CBZ‐AAN‐Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions 下载免费PDF全文
Hongyuan Chen Xiao Liu Eric S. Clayman Fangyuan Shao Manshan Xiao Xuyan Tian Wuyu Fu Caiyun Zhang Bibo Ruan Pengjun Zhou Zhong Liu Yifei Wang Wen Rui 《Chemical biology & drug design》2015,86(4):589-598
Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side‐effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N‐benzyloxycarbonyl‐Ala‐Ala‐Asn‐Doxorubicin (CBZ‐AAN‐Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain‐specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ‐AAN‐Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain. 相似文献
3.
Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells 下载免费PDF全文
Katharina Hammer Adam Kazcorowski Li Liu Michael Behr Peter Schemmer Ingrid Herr Dirk M. Nettelbeck 《International journal of cancer. Journal international du cancer》2015,137(4):978-990
Oncolytic viruses have demonstrated in pre‐clinical and clinical studies safety and a unique pleiotropic activity profile of tumor destruction. Yet, their delivery suffers from virus inactivation by blood components and sequestration to healthy tissues. Therefore, mesenchymal stromal cells (MSCs) have been applied as carrier cells for shielded virus delivery to tumors after ex vivo infection with oncolytic viruses. However, infection and particle production by MSCs have remained unsatisfying. Here, we report engineered oncolytic adenoviruses (OAds) for improved virus production and delivery by MSCs. OAds are uniquely amenable to molecular engineering, which has facilitated improved tumor cell destruction. But for MSC‐mediated regimens, OAd engineering needs to achieve efficient infection and replication in both MSCs and tumor cells. We show that an Ad5/3 chimeric OAd capsid, containing the adenovirus serotype 3 cell‐binding domain, strongly increases the entry into human bone marrow‐derived MSCs and into established and primary pancreatic cancer cells. Further, we reveal that OAd with engineered post‐entry functions—by deletion of the anti‐apoptotic viral gene E1B19K or expression of the death ligand TRAIL—markedly increased virus titers released from MSCs, while MSC migration was not hampered. Finally, these virus modifications, or viral expression of FCU1 for local 5‐FC prodrug activation, improved tumor cell killing implementing complementary cytotoxicity profiles in a panel of pancreatic cancer cell cultures. Together, our study establishes post‐entry modification of OAd replication for improving virus delivery by carrier cells and suggests a panel of optimized OAds for future clinical development in personalized treatment of pancreatic cancer. 相似文献
4.
《Expert opinion on biological therapy》2013,13(2):239-252
High grade gliomas in adults are devastating diseases, with very poor survival despite their lack of distant metastases. Local treatments, such as surgical resection and stereotactic radiosurgery, have been most successful, whereas systemic therapy (for example, chemotherapy and immunotherapy) have been rather disappointing. Several gene therapy systems have been successful in controlling or eradicating these tumours in animal models and are now being tested as a logical addition to current clinical management. This review describes the gene therapy clinical protocols that have been completed or that are ongoing for human gliomas. These include the prodrug activating system, herpes simplex thymidine kinase (HSVtk)/ganciclovir (GCV), utilising either retrovirus vector producer cells or adenovirus vectors; adenovirus mediated p53 gene transfer; adenovirus mediated IFN-β gene transfer and oncolytic herpes virus and adenovirus vectors. To date, all of the clinical studies have used direct injection of the vector into the glioma. The Phase I clinical studies have demonstrated low to moderate toxicity and variable levels of gene transfer and in some cases anti-tumour effect. Future directions will rely upon improvements in gene delivery as well as gene therapies and combinations of gene therapy with other treatment modalities. 相似文献
5.
《Expert opinion on therapeutic targets》2013,17(1):23-25
Peptide deformylase (PDF) catalyses the hydrolytic removal of the N-terminal formyl group from nascent ribosome-synthesised polypeptides. Its activity is essential and it is present in all eubacteria. It is also present in the organelles of some eukaryotes. PDF represents a novel class of mononuclear iron protein, utilising an Fe2+ ion to catalyse the hydrolysis of an amide bond. Due to its extreme lability, isolation and characterisation of PDF was not possible until very recently. This review will discuss the recent progress in the elucidation of the the structure and function of PDF, evaluating its suitability as a target for antibiotic design and summarising the current approaches to designing drugs that target PDF. 相似文献
6.
Ursula Altanerova Jana Jakubechova Katarina Benejova Petra Priscakova Martin Pesta Pavel Pitule Ondrej Topolcan Juraj Kausitz Martina Zduriencikova Vanda Repiska Cestmir Altaner 《International journal of cancer. Journal international du cancer》2019,144(4):897-908
The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT-MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT-MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5-fluorocytosine (5-FC) effectively triggered dose-dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5-FC to 5-fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT-MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential. 相似文献
7.
Qingjie Liu Douglas G. Batt Carolyn A. Weigelt Shiuhang Yip Dauh-Rurng Wu Max Ruzanov John S. Sack Jinhong Wang Melissa Yarde Sha Li David J. Shuster Jenny H. Xie Tara Sherry Mary T. Obermeier Aberra Fura Kevin Stefanski Georgia Cornelius Purnima Khandelwal Joseph A. Tino John E. Macor Luisa Salter-Cid Rex Denton Qihong Zhao T. G. Murali Dhar 《ACS medicinal chemistry letters》2020,11(12):2510
Employing a virtual screening approach, we identified the pyroglutamide moiety as a nonacid replacement for the cyclohexanecarboxylic acid group which, when coupled to our previously reported conformationally locked tricyclic core, provided potent and selective RORγt inverse agonists. Structure–activity relationship optimization of the pyroglutamide moiety led to the identification of compound 18 as a potent and selective RORγt inverse agonist, albeit with poor aqueous solubility. We took advantage of the tertiary carbinol group in 18 to synthesize a phosphate prodrug, which provided good solubility, excellent exposures in mouse PK studies, and significant efficacy in a mouse model of psoriasis. 相似文献
8.
Hepatocellular carcinoma (HCC) is a serious cancer with high mortality worldwide. Gemcitabine (GEM) is easily degraded in the circulation and has no tumor-targeted effect. In our previous research, an amphiphilic GEM derivative, cyclic phosphoryl N-dodecanoyl gemcitabine (CPDG) was prepared based on the techniques of HepDirect prodrug and self-assembled drug delivery systems (SADDS), which self-assembled into the stable nanoassemblies in water. In this study, the long-circulating nanoassemblies of CPDG/CHS-PEG1500 (9:1, mol/mol) were prepared for HCC treatment. In vitro and in vivo studies of the long-circulating CPDG nanoassemblies were explored. The degradation rates of CPDG depended on the media. CPDG showed much faster degradation in the acidic environment (pH 2.0) than the weak acidic and neutral media (pH 5.0, pH 7.4). However, the degradation half-life (t1/2) of CPDG was about 43 h in the mouse plasma, longer than the t1/2 at pH 2.0. Therefore, the long-circulating CPDG nanoassemblies could keep stable before reaching the targets in vivo. In the biodistribution study, the long-circulating CPDG nanoassemblies were bolus intravenously (i.v.) injected into the hepatocellular tumor-bearing mice. The distribution of CPDG in the tumors was much higher than that in the blood, indicating the tumor targeting of the long-circulating nanoassemblies. In the pharmacodynamic study, the long-circulating CPDG nanoassemblies were i.v. injected into the tumor-bearing mice with doses of (37.5, 75 μmol/kg) compared with GEM (150 μmol/kg). The mice were injected once every 3 days for totally 3 times. The long-circulating nanoassemblies nearly always showed the higher anti-cancer effects than GEM. The tumor inhibitory rates of GEM, the long circulating CPDG nanoassemblies (37.5, 75 μmol/kg) were 49.54, 42.97, 65.10%, respectively. Therefore, the long-circulating CPDG nanoassemblies had the much higher anti-cancer effect than GEM. The long-circulating CPDG nanoassemblies are promising nanomedicines to treat HCC. The combination design of tumor-targeted nanoassemblies based on HepDirect prodrug technique and SADDS theory is an effective method to modify the pharmacologically active nucleosides to treat some liver diseases. 相似文献
9.
《Expert opinion on therapeutic patents》2013,23(3):277-280
Prodrugs are bioreversible derivatives of drug molecules used to overcome some barriers to the utility of the parent drug molecule. These barriers include, but are not limited to, solubility, permeability, stability, presystemic metabolism and targeting limitations. The patent literature shows a dramatic increase in numbers of prodrug patents (> 2000% increase in 2002 compared to 1993), with claims for cancer treatment comprising 37% of these. This increase is largely due to the rise from North American-based multinationals and some smaller drug delivery companies mirroring the overall trend. In 2001 and 2002, 14% of all new approved chemical drugs were prodrugs. It appears that prodrugs to overcome barriers to the delivery of problematic drug candidates are becoming an integral part of the drug discovery paradigm. 相似文献
10.
Jun Li Yedan Zhu Miaohong Xie Qian Zhang Wenting Du 《Chemical biology & drug design》2019,94(4):1760-1767
Four compounds T1 , T2 , T3 , and T4 were designed and synthesized as Vorinostat and Belinostat derivatives being the target water‐soluble prodrugs. The water solubility of Vorinostat derivatives, T1 and T2 , exhibited 400‐ to 600‐fold higher than that of Vorinostat, and Belinostat derivatives, T3 and T4 , showed 600‐ to 750‐fold higher than that of Belinostat. Four compounds were evaluated for their inhibitory activities against tumor cell lines HT‐29 and Hut‐78 in the absence or presence of β‐D‐glucuronidase. The inhibitory effects of T1 and T2 were comparable to Vorinostat in the presence of β‐D‐glucuronidase, but were higher than 10 μM in the absence of β‐D‐glucuronidase. Therefore, T1 and T2 are promising candidates for in vivo investigations with high potential to be the target water‐soluble prodrugs. IC50 values of Belinostat derivatives T3 and T4 were not affected by β‐D‐glucuronidase, but T3 and T4 had the excellent cell proliferation inhibition on Hut‐78. 相似文献