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Conclusions We conclude that therapy with PHA 739358 may of


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СообщениеДобавлено: 07:08 20-11-2015    Заголовок сообщения: Conclusions We conclude that therapy with PHA 739358 may of Ответить с цитатой

Despite this, MEK inhibitors are likely to have a role in the treatment of cancers with constitutive MAPK signaling from onco genic mutations upstream of MEK. In particular the combination of MEK and RAF inhibitors may be benefi cial by inducing higher MAPK inhibition in mutant cells and therefore lowering AP24534 Src-bcr-Abl 阻害剤 the cancer escape mechan isms and also decreasing toxicities from paradoxical MAPK activation, such as the development of cuta neous squamous cell carcinomas. The majority of uveal melanomas bear a mutually ex clusive activating mutation in either GNAQ or GNA11, resulting in overlapping functions in melanoma cells with the constitutive upregulation of the MAPK path way. In preclinical models it was shown that at least events, and may be the reason of the discrepancy in results.<br><br> These results raise the point AT7519 that earlier PET scans with these tracers to detect early pharmacody namic changes may not fully predict the later restaging imaging CT scan results. In conclusion, inhibition of oncogenic MAPK signaling through MEK1 and MEK2 by TAK733 results in antitu mor activity in vitro against a large subset of melanoma cell lines. We confirmed the previously reported cytotoxic effect of a MEK inhibitor against cell lines with BRAFV600E mutations, but in addition the cytotoxic activity was evi dent in a high proportion of melanoma cell lines with NRAS, GNAQ or GNA11 driver mutations. The antiproli ferative and cell metabolism effects of this MEK inhibitor against melanoma cell lines can be detected with metabolic probes that could be tested with caution in the clinical development of this agent using PET imaging.<br><br> Material and methods Reagents and cell lines the GNAQ mutation resulted in sensitivity to down stream blocking of the MAPK pathway with a MEK in hibitor. Our data demonstrating the sensitivity Akt3 阻害剤 of uveal melanoma cell lines to TAK733 provides further evidence that it may be a clinical strategy to use MEK inhibitors to treat metastatic uveal melanomas. However, the same issues of a lack of correlation between the in vitro and clinical results when blocking oncogenic MAPK signal ing using MEK inhibitors may apply to uveal melanomas. The differential uptake of 3H radiolabeled com pounds that are trapped intracellularly upon metabolic processing allows testing their potential future use as PET probes in the clinical development of a new agent.<br><br> It is anticipated that these radiolabeled metabolic probes can provide non invasive pharmacodynamic in formation with the use of clinical PET scanners. In our studies, the highly sensitive cell lines had a decrease in the uptake of radiolabeled thymidine and deoxy glucose that seemingly correlated with the cell viability and cell cycle results. However, there were variable changes in the highly resistant cell lines that did not directly correlate with the cell viability assay results. The metabolic tracer uptake studies were performed at a slightly earlier time point than the proliferationviability assays to capture earlier TAK 733 was obtained under a materials transfer agree ment from Millennium Pharmaceuticals, Inc. and dissolved in dimethyl sulfoxide to a stock concentration of 10 mM.
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