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M Rouquayrol B Gaucher J Greiner A M Aubertin P Vierling R Guedj 《Carbohydrate research》2001,336(3):161-180
With the aim at improving the transport of the current HIV protease inhibitors across the intestinal and blood brain barriers and their penetration into the central nervous system, the synthesis of various acyl and carbamatoyl glucose-containing prodrugs derived from saquinavir, indinavir and nelfinavir, their in vitro stability with respect to hydrolysis, and their anti-HIV activity have been investigated. D-Glucose, which is actively transported across these barriers, was connected through its 3-hydroxyl to these antiproteases via a linker. The liberation of the active free drug during the incubation time of the prodrugs with the cells was found to be crucial for HIV inhibition. The labile ester linking of the glucose-containing moiety to the peptidomimetic hydroxyl of saquinavir or to the indinavir C-8 hydroxyl, which is not part of the transition state isostere, is not an obstacle for anti-HIV activity. This is not the case for its stable carbamate linking to the peptidomimetic hydroxyl of saquinavir, indinavir and nelfinavir. The chemical stability with respect to hydrolysis of some of the saquinavir and indinavir prodrugs reported here, the liberation rate of the active free drug and the HIV inhibitory potency are acceptable for an in vivo use of these prodrugs. These glucose-linked ester and carbamate prodrugs display a promising therapeutic potential provided that their bioavailability, penetration into the HIV sanctuaries, and/or the liberation of the active free drug from the carbamate prodrugs are improved. Furthermore, no cytotoxicity was detected for the prodrugs for concentrations as high as 10 or even 100 microM, thus indicating an encouraging therapeutic index. 相似文献
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Martín-Cófreces NB Sancho D Fernández E Vicente-Manzanares M Gordón-Alonso M Montoya MC Michel F Acuto O Alarcón B Sánchez-Madrid F 《Journal of immunology (Baltimore, Md. : 1950)》2006,176(7):4201-4207
The translocation of the microtubule-organizing center (MTOC), its associated signaling complex, and the secretory apparatus is the most characteristic early event that involves the tubulin cytoskeleton of T or NK cells after their interaction with APC or target cells. Our results show that Fyn kinase activity is essential for MTOC reorientation in an Ag-dependent system. Moreover, T cells from Fyn-deficient mice are unable to rearrange their tubulin cytoskeleton in response to anti-CD3-coated beads. Analysis of conjugates of T cells from transgenic OT-I mice with dendritic cells revealed that an antagonist peptide induces translocation of the MTOC, and that this process is impaired in T cells from Fyn(-/-) OT-I mice. In addition, Fyn deficiency significantly affects the MTOC relocation mediated by agonist peptide stimulation. These results reveal Fyn to be a key regulator of tubulin cytoskeleton reorganization in T cells. 相似文献
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Noa Madar-Balakirski Catherine Tempel-Brami Vyacheslav Kalchenko Ori Brenner David Varon Avigdor Scherz Yoram Salomon 《PloS one》2010,5(4)
Background
Antiangiogenic and anti-vascular therapies present intriguing alternatives to cancer therapy. However, despite promising preclinical results and significant delays in tumor progression, none have demonstrated long-term curative features to date. Here, we show that a single treatment session of Tookad-based vascular targeted photodynamic therapy (VTP) promotes permanent arrest of tumor blood supply by rapid occlusion of the tumor feeding arteries (FA) and draining veins (DV), leading to tumor necrosis and eradication within 24–48 h.Methodology/Principal Findings
A mouse earlobe MADB106 tumor model was subjected to Tookad-VTP and monitored by three complementary, non-invasive online imaging techniques: Fluorescent intravital microscopy, Dynamic Light Scattering Imaging and photosensitized MRI. Tookad-VTP led to prompt tumor FA vasodilatation (a mean volume increase of 70%) with a transient increase (60%) in blood-flow rate. Rapid vasoconstriction, simultaneous blood clotting, vessel permeabilization and a sharp decline in the flow rates then followed, culminating in FA occlusion at 63.2 sec±1.5SEM. This blockage was deemed irreversible after 10 minutes of VTP treatment. A decrease in DV blood flow was demonstrated, with a slight lag from FA response, accompanied by frequent changes in flow direction before reaching a complete standstill. In contrast, neighboring, healthy tissue vessels of similar sizes remained intact and functional after Tookad-VTP.Conclusion/Significance
Tookad-VTP selectively targets the tumor feeding and draining vessels. To the best of our knowledge, this is the first mono-therapeutic modality that primarily aims at the larger tumor vessels and leads to high cure rates, both in the preclinical and clinical arenas. 相似文献79.
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