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Selective Targeting (selective + targeting)
Selected AbstractsSELECTIVE TARGETING OF THE TUMOUR VASCULATURE,ANZ JOURNAL OF SURGERY, Issue 11 2008Lie S. Chan Selective targeting of the tumour vasculature in the treatment of solid organ malignancies is an alternative to conventional chemotherapy treatment. As the tumour progressively increases in size, angiogenesis or the formation of new vasculature is essential to maintain the tumour's continual growth and survival. Therefore disrupting this angiogenic process or targeting the neovasculature can potentially hinder or prevent further tumour expansion. Many anti angiogenic agents have been investigated with many currently in clinical trials and exhibiting varied results. Vascular disrupting agents such as the Combretastatins and OXi 4503 have shown promising preclinical results and are currently being examined in clinical trials. [source] Upregulation of K2P5.1 potassium channels in multiple sclerosisANNALS OF NEUROLOGY, Issue 1 2010Stefan Bittner BSc Objective Activation of T cells critically depends on potassium channels. We here characterize the impact of K2P5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell,mediated autoimmune disorder, multiple sclerosis (MS). Methods Expression of K2P5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K2P5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. Results Human T cells constitutively express K2P5.1. After T-cell activation, a significant and time-dependent upregulation of K2P5.1 channel expression was observed. Pharmacological blockade of K2P5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K2P5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K2P5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K2P5.1 upregulation in CD4+ and CD8+ T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8+ T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K2P5.1 levels. Furthermore, K2P5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens. Interpretation Selective targeting of K2P5.1 may hold therapeutic promise for MS and putatively other T-cell,mediated disorders. ANN NEUROL 2010;68:58,69 [source] SELECTIVE TARGETING OF THE TUMOUR VASCULATURE,ANZ JOURNAL OF SURGERY, Issue 11 2008Lie S. Chan Selective targeting of the tumour vasculature in the treatment of solid organ malignancies is an alternative to conventional chemotherapy treatment. As the tumour progressively increases in size, angiogenesis or the formation of new vasculature is essential to maintain the tumour's continual growth and survival. Therefore disrupting this angiogenic process or targeting the neovasculature can potentially hinder or prevent further tumour expansion. Many anti angiogenic agents have been investigated with many currently in clinical trials and exhibiting varied results. Vascular disrupting agents such as the Combretastatins and OXi 4503 have shown promising preclinical results and are currently being examined in clinical trials. [source] Selective targeting of a laccase from Stachybotrys chartarum covalently linked to a carotenoid-binding peptideCHEMICAL BIOLOGY & DRUG DESIGN, Issue 1 2004G.G. Janssen Abstract:, A two-step targeting strategy was used to identify improved laccases for bleaching carotenoid-containing stains on fabric. We first applied a modified phage display technique to identify peptide sequences capable of binding specifically to carotenoid stains and not to fabric. Prior deselection on the support on which the carotenoid was localized, increased stringency during the biopanning target selection process, and analysis of the phage peptides' binding to the target after acid elution and polymerase chain reaction (PCR) postacid elution, were used to isolate phage peptide libraries with increased binding selectivity and affinity. Peptide sequences were selected based on identified consensus motifs. We verified the enhanced carotenoid-binding properties of the peptide YGYLPSR and subsequently cloned and expressed C-terminal variants of laccase from Stachybotrys chartarum containing carotenoid-binding peptides YGYLPSR, IERSAPATAPPP, KASAPAL, CKASAPALC, and SLLNATK. These targeted peptide,laccase fusions demonstrate enhanced catalytic properties on stained fabrics. [source] CTLA-4 co-receptor impacts on the function of Treg and CD8+ T-cell subsetsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Christopher E. Rudd Abstract CTLA-4 has potent regulatory effects on the threshold of T-cell signalling and, in the process, guards against the development of hyper-proliferation and autoimmunity. Despite this, the role of CTLA-4 on specific T-cell subsets has been unclear. Such studies could shed light on both the function of CTLA-4, and on the contribution of the subsets to the disease phenotype of the Ctla4,/, mouse. Recently, a role for this co-receptor in the function of Treg has been outlined and, in this issue of the European Journal of Immunology, the selective targeting of the T-box transcription factor Eomes by CTLA-4 in the regulation of CD8+ cytolytic T-cell (CTL) effector function is shown. Together, these papers shed light on the role of CTLA-4 in different T-cell subsets. [source] Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication-competent CD95L adenovirusEXPERIMENTAL DERMATOLOGY, Issue 8 2010Lothar F. Fecker Please cite this paper as: Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication-competent CD95L adenovirus. Experimental Dermatology 2010; 19: e56,e66. Abstract:, The high mortality of melanoma demands the development of new strategies, and gene therapy may be considered provided improvements in efficacy and selectivity. Overexpression of the death ligand CD95L/FasL has been shown in previous studies as highly effective for apoptosis induction in melanoma cells. For efficient and selective targeting of melanoma, a conditional replication-competent adenoviral vector was constructed (Ad5-FFE-02), which drives CD95L expression by a tetracycline-inducible promoter. For restricting its replication to melanoma cells, the adenoviral E1A gene is controlled by a tyrosinase-derived promoter. Furthermore, adenoviral E1B was deleted and a mutated E1A was used to preferentially support replication in tumor cells. Proving its high selectivity and efficiency, strong expression of E1A and doxycycline-dependent induction of CD95L were characteristic for tyrosinase-positive melanoma cells after Ad5-FFE-02 transduction, whereas absent in non-melanoma cell lines. Importantly, Ad5-FFE-02-mediated cell lysis was restricted to melanoma cells, and induction of apoptosis was found only in tyrosinase and CD95 expressing cells. Finally, the combination of adenoviral replication and CD95L-mediated apoptosis resulted in an enhanced repression of melanoma cell growth. This new adenoviral vector may provide a basis for an efficient targeting of melanoma. [source] Anti-disialosyl antibodies mediate selective neuronal or Schwann cell injury at mouse neuromuscular junctionsGLIA, Issue 3 2005Susan K. Halstead Abstract The human paralytic neuropathy, Miller Fisher syndrome (MFS) is associated with autoantibodies specific for disialosyl epitopes on gangliosides GQ1b, GT1a, and GD3. Since these gangliosides are enriched in synaptic membranes, anti-ganglioside antibodies may target neuromuscular junctions (NMJs), thereby contributing to disease symptoms. We have shown previously that at murine NMJs, anti-disialosyl antibodies induce an ,-latrotoxin-like effect, electrophysiologically characterized by transient massive increase of spontaneous neurotransmitter release followed by block of evoked release, resulting in paralysis of the muscle preparation. Morphologically, motor nerve terminal damage, as well as perisynaptic Schwann cell (pSC) death is observed. The relative contributions of neuronal and pSC injury to the paralytic effect and subsequent repair are unknown. In this study, we have examined the ability of subsets of anti-disialosyl antibodies to discriminate between the neuronal and glial elements of the NMJ and thereby induce either neuronal injury or pSC death. Most antibodies reactive with GD3 induced pSC death, whereas antibody reactivity with GT1a correlated with the extent of nerve terminal injury. Motor nerve terminal injury resulted in massive uncontrolled exocytosis with paralysis. However, pSC ablation induced no acute (within 1 h) electrophysiological or morphological changes to the underlying nerve terminal. These data suggest that at mammalian NMJs, acute pSC injury or ablation has no major deleterious influence on synapse function. Our studies provide evidence for highly selective targeting of mammalian NMJ membranes, based on ganglioside composition, that can be exploited for examining axonal,glial interactions both in disease states and in normal NMJ homeostasis. © 2005 Wiley-Liss, Inc. [source] Microtubules: dynamics, drug interaction and drug resistance in LeishmaniaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2002K. G. Jayanarayan MS (Pharm) Summary Microtubules are cytoskeletal polymers essential for the survival of all eukaryotes. These proteins are the proposed cellular targets of many anticancerous, antifungal and antihelminthic drugs. Sufficient differences exist between the microtubules of kinetoplastid parasites like Leishmania and humans to explore the selective targeting of these proteins for therapeutic purposes. This review describes the basic structure of microtubules and its dynamics in general, with specific insights into leishmanial microtubules, the salient features of microtubule,drug interactions including the specificity of certain drugs for parasitic microtubules. Chemotherapy against leishmanial parasites is failing because of the emergence of drug resistant strains. The possible mechanisms of resistance to antimicrotubule agents along with insights into the role of microtubules in mediating drug resistance in Leishmania are discussed. [source] Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiaeAGING CELL, Issue 4 2009Ashley L. Alvers Summary Following cessation of growth, yeast cells remain viable in a nondividing state for a period of time known as the chronological lifespan (CLS). Autophagy is a degradative process responsible for amino acid recycling in response to nitrogen starvation and amino acid limitation. We have investigated the role of autophagy during chronological aging of yeast grown in glucose minimal media containing different supplemental essential and nonessential amino acids. Deletion of ATG1 or ATG7, both of which are required for autophagy, reduced CLS, whereas deletion of ATG11, which is required for selective targeting of cellular components to the vacuole for degradation, did not reduce CLS. The nonessential amino acids isoleucine and valine, and the essential amino acid leucine, extended CLS in autophagy-deficient as well as autophagy-competent yeast. This extension was suppressed by constitutive expression of GCN4, which encodes a transcriptional regulator of general amino acid control (GAAC). Consistent with this, GCN4 expression was reduced by isoleucine and valine. Furthermore, elimination of the leucine requirement extended CLS and prevented the effects of constitutive expression of GCN4. Interestingly, deletion of LEU3, a GAAC target gene encoding a transcriptional regulator of branched side chain amino acid synthesis, dramatically increased CLS in the absence of amino acid supplements. In general, this indicates that activation of GAAC reduces CLS whereas suppression of GAAC extends CLS in minimal medium. These findings demonstrate important roles for autophagy and amino acid homeostasis in determining CLS in yeast. [source] Folate receptor , as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patientsARTHRITIS & RHEUMATISM, Issue 1 2009Joost W. Van Der Heijden Objective To determine the expression of folate receptor , (FR,) in synovial biopsy tissues and peripheral blood lymphocytes from rheumatoid arthritis (RA) patients and to identify novel folate antagonists that are more selective in the targeting and internalization of FR, than methotrexate (MTX). Methods Immunohistochemistry and computer-assisted digital imaging analyses were used for the detection of FR, protein expression on immunocompetent cells in synovial biopsy samples from RA patients with active disease and in noninflammatory control synovial tissues. FR, messenger RNA (mRNA) levels were determined by reverse transcription,polymerase chain reaction analysis. Binding affinities of FR, for folate antagonists were assessed by competition experiments for 3H-folic acid binding on FR,-transfected cells. Efficacy of FR,-mediated internalization of folate antagonists was evaluated by assessment of antiproliferative effects against FR,-transfected cells. Results Immunohistochemical staining of RA synovial tissue showed high expression of FR, on macrophages in the intimal lining layer and synovial sublining, whereas no staining was observed in T cell areas or in control synovial tissue. Consistently, FR, mRNA levels were highest in synovial tissue extracts and RA monocyte-derived macrophages, but low in peripheral blood T cells and monocytes. Screening of 10 new-generation folate antagonists revealed 4 compounds for which FR, had a high binding affinity (20,77-fold higher than for MTX). One of these, the thymidylate synthase inhibitor BCG 945, displayed selective targeting against FR,-transfected cells. Conclusion Abundant FR, expression on activated macrophages in synovial tissue from RA patients deserves further exploration for selective therapeutic interventions with high-affinity,binding folate antagonists, of which BCG 945 may be a prototypical representative. [source] Predominant Expression of Mutant EGFR (EGFRvIII) is Rare in Primary GlioblastomasBRAIN PATHOLOGY, Issue 2 2004Wojciech Biernat EGFR amplification is a frequent genetic alteration in primary (de novo) glioblastomas, and is often associated with structural alterations. Most common is variant III (EGFRvIII), which results from a non-random 801 bp in-frame deletion of exons 2 to 7 of the EGFR gene. We assessed amplification and overexpression of EGFRvIII and wild-type EGFR in 30 glioblastoma biopsies. Immunohistochemically, EGFR overexpression was observed in 20 (67%) of 30 glioblastomas. Eight (27%) cases also showed immunoreactivity to an EGFRvIII antibody. In 6 of these cases, the pattern of EGFR and EGFRvIII overexpression was compared in serial sections: In 4 cases, areas with immunoreactivity to EGFRvIII largely coincided with wild-type EGFR expression. In the other 2 cases, the areas immunoreactive to EGFRvIII were significantly less extensive than EGFR-positive areas. To assess whether EGFRvIII is predominantly amplified in tumors with concurrent wild-type EGFR amplification, we carried out real-time quantitative PCR using 2 sets of primers located in exon 2 and intron 15 of the EGFR gene. A>5-fold ratio of relative copy numbers between intron 15 (present both in wild-type EGFR and EGFRvIII) and exon 2 (present only in wild-type EGFR, but missing in EGFRvIII) suggested predominant amplification of EGFRvIII in only 3 (10%) of 30 glioblastomas. The observation that intratumoral wild-type EGFR overexpression is often more extensive and that predominant amplification of EGFRvIII is a rare event would limit the effectiveness of therapeutic approaches based on selective targeting of EGFRvIII. [source] Tumor hypoxia: A target for selective cancer therapyCANCER SCIENCE, Issue 12 2003Shinae Kizaka-Kondoh Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO2<0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties. [source] | |||||||||||||