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Receptor Profile (receptor + profile)
Selected AbstractsCharacterization of calcium-independent purinergic receptor-mediated apoptosis in hormone-refractory prostate cancerBJU INTERNATIONAL, Issue 3 2008Majid Shabbir OBJECTIVE To investigate the nature of purinergic signalling in hormone-refractory prostate cancer (HRPC) cells in vitro, as extracellular ATP inhibits the growth of HRPC in vitro via the activation of P2 purinergic receptors, and to characterize which P2 receptors subtypes and secondary mechanisms are involved. MATERIALS AND METHODS The effect of extracellular ATP on HRPC cell lines PC-3 and DU-145, and the normal prostate cell line PNT-2, were investigated. Reverse-transcription polymerase chain reaction was used to assess P2 purinergic receptors, which were pharmacologically characterized using various receptor agonists and antagonists. The effect of ATP on intracellular Ca2+ concentration ([Ca2+]i) was examined to asses its role in growth inhibition. The effect of combining ATP with the chemotherapeutic drug mitoxantrone was also assessed. RESULTS PC-3 cells expressed mRNA for P2X4,5,7, P2Y1,2,4,6; DU-145 cells expressed mRNA for P2X4,5, P2Y1,2,4,6,11; PNT-2 cells expressed mRNA for P2X4,5,7 and P2Y1,2,4,6,11. ATP (10,4m) inhibited HRPC PC-3 cell growth by ,,90%, an effect partially inhibited by the nonselective P2 receptor antagonists pyridoxal-5,-phosphate-6-azophenyl-2,,4, disulphonic acid (PPADS) and suramin. The order of potency of agonists was: adenosine 5,-O-(3 thiotriphosphate) > ATP > benzoyl benzoyl ATP >> 2-methylthio ATP. DU-145 cells responded similarly. Pharmacological profiling implicated P2X5 and/or P2Y11 receptors in the antineoplastic response in HRPC. ATP induced apoptosis in a [Ca2+]i -independent mechanism. ATP was significantly less effective on PNT-2 cells, which also had a different order of agonist potency. ATP combined with mitoxantrone in an additive manner in HRPC. CONCLUSIONS ATP effectively reduces growth of HRPC cells via calcium-independent apoptosis. Pharmacological profiling indicates P2X5 and/or P2Y11 receptors in this process, with a different functional purinergic receptor profile and sensitivity in normal vs cancer cells. [source] Differential cytotoxicity of novel somatostatin and dopamine chimeric compounds on bronchopulmonary and small intestinal neuroendocrine tumor cell linesCANCER, Issue 4 2008Mark Kidd PhD Abstract BACKGROUND. Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not significantly altered (overall 67%, 5-year survival) in 30 years (1973-2004), whereas the incidence has increased (, 1000%) in the same time frame. No effective or specific antineoplastic agent is available for treatment, although somatostatin analogs inhibit tumor secretion. Given the coexistence of somatostatin and dopamine regulatory receptors on NET cells, the antiproliferative efficacy as well as the signaling and transcriptional targets of their ligands were evaluated. METHODS. The cytotoxic effects of 12 somatostatin/dopamine compounds were evaluated in 3 NET cell lines, and real-time polymerase chain reaction and enzyme-linked immunoadsorbent assay studies were performed to delineate antiproliferative signaling pathways. RESULTS. The atypical BP-NET, NCI-H720, was most sensitive to the sst5 analog BIM23206 (half-maximal concentration, 2.4 pM) and demonstrated similar sensitivity to lanreotide and the sst2 analog BIM23120. The typical BP-NET, NCI-H727, was most sensitive to BIM23120 (0.7 nM) and to the pan-somatostatin receptor analog (BIM23A779). The GI-NET, KRJ-I, was most sensitive to sst2,5 analogs lanreotide (1 nM) and BIM23244 (7.4 nM). Lanreotide activated extracellular signal regulated kinase-1/2 phosphorylation and p21WAF1/CIP1 transcription, but inhibited Ki-67 transcription. NCI-H720 was most sensitive to the sst2,5 - and D2 -selective compound BIM23A761 (4.2 nM), as was NCI-H727 (5.5 nM). KRJ-I did not respond to any chimeric analog. BIM23A761 activated c-Jun N-terminal kinase signaling and caused inhibition of Ki-67 transcription. P21WAF1/CIP1 transcription was activated only in NCI-H727 cells. CONCLUSIONS. The different responses of each individual cell line suggested that NETs from different locations arising from different neuroendocrine cells may require cell-specific antiproliferative agents based on the unique receptor profile of individual lesions. Cancer 2008. © 2008 American Cancer Society. [source] An Overview of SR121463, a Selective Non-Peptide Vasopressin V2 Receptor AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 3 2001C. Serradeil-Le Gal ABSTRACT SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V2 receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V2 receptors and exhibits a remarkably selective V2 receptor profile. SR121463 and [3H]SR121463 are used, therefore, as selective probes for characterization and labeling of V2 receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V2 receptor mutant. In vitro, SR1 21463 rescued misfolded V2 AVP receptor mutants by increasing cell surface expression and restoring V2 function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V2 (or V2 -like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V2 receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V2 receptors. Pure V2 receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V2 receptors (e.g., glaucoma). [source] A Korean experience with chronic actinic dermatitis during an 18-year period: meteorological and photoimmunological aspectsPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 6 2009Kyu-Won Choi Background and purpose: The authors noted that chronic actinic dermatitis (CAD) increased in connection with increased sun exposure and believed that there may be a correlation between the two. The purpose of this study was to determine the relationship between increased sun exposure and CAD. We also applied a clinical severity scoring system to determine the correlation with various laboratory parameters. Materials and methods: We investigated trends in sun exposure in Pusan during an 18-year period. We conducted photopatch/patch testing in 51 CAD patients. We also determined the total IgE, percentage of eosinophils, and chemokine receptor profiles in the peripheral blood and analyzed correlations between laboratory data and the clinical severity of CAD. Results: A close correlation was demonstrated between the number of CAD patients and increased sun exposure. Positive patch test reactions and positive photopatch reactions were observed in 35 and 41 of the 51 tested patients, respectively. The total IgE levels were higher in the severe group than in the others. CCR4 expression increased in parallel with clinical severity. Conclusion: Korean patients may have increased susceptibility to CAD with increased sun exposure. We believe that the majority of the CAD patients tested had photoallergy and contact allergy. The clinical severity seemed to correlate well with the total IgE level and CCR4 expression. [source] | ||||||||||