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 Post subject: This is contravened by HAT, which opens the structure
PostPosted: Mon Dec 16, 2013 10:11 pm 
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Joined: Mon Nov 18, 2013 9:15 pm
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The mice オーダー ABT-888 had small tumors with little invasion and few or no liver metastases. The present findings and published reports indicate that treatment with inhibitors of VEGF signaling prolongs the survival of RIP Tag2 mice. Although the survival benefit would seem contradictory to greater invasiveness and metastasis in these mice, overall survival reflects the balance of competing effects of treatment on tumor growth, invasion, and metastasis. In the several week timeframe of the experiments, the beneficial effects of VEGF blockade on tumor growth outweighed the negative effects of greater invasion and metastasis. Treatment with sunitinib provided greater survival benefit in RIP Tag2 mice than was found with the anti VEGF antibody.<br><br> In buy Afatinib our experiments, 80% of mice treated with sunitinib survived from age 14 to 17 weeks, compared to 50% treated with anti VEGF antibody. The multi targeted activity of sunitinib is among the contributing factors. Also, sunitinib treatment began at age 12 weeks in an earlier report, but anti VEGF antibody treatment began in our studies at age 14 weeks, when tumors were more advanced. Another factor is that an immune response to the goat anti VEGF antibody in mice could have reduced VEGF blocking activity over time. The synergistic effects of inhibiting c Met and VEGF signaling together reflect the complementary features of the two pathways as drug targets. Still to be determined in elucidating the underlying mechanism of synergy is whether activation of c Met signaling in invasive RIP Tag2 tumors is ligand independent, as suggested by our in vitro studies of hypoxic tumor cells.<br><br> Interactions between c Met and VEGFR could also involve heterodimer formation, kinase transphosphorylation, cross talk between signaling pathways, or other mechanisms. The hypothesis オーダー AG-1478 that c Met is necessary and sufficient for promotion of tumor aggressiveness by inhibition of VEGF signaling, which we tested by pharmacological approaches, could also be addressed by genetic overexpression or deletion of c Met. From published evidence, c Met activation would be expected to promote tumor aggressiveness and deletion to have the opposite effect. Overall, our findings are consistent with previous evidence of exaggerated tumor invasiveness and metastasis after inhibition of VEGF signaling.<br><br> Data from studies using the anti VEGF antibody indicate that the tumor aggressiveness observed previously is not dependent on an off target action of sunitinib or a peculiarity of the anti VEGFR 2 antibody DC101. If present in humans, this consequence of selective VEGF blockade could contribute to resistance to angiogenesis inhibitors. Multiple lines of evidence implicate hypoxia, HIF 1, and c Met activation in the tumor aggressiveness. Blockade of c Met and VEGF signaling together either by a combination of two selective agents or by a single multi targeted agent reduced tumor invasion and metastasis, and prolonged overall survival. Concurrent inhibition of the two signaling pathways had the favorable growth slowing effects of angiogenesis inhibition and vascular pruning without the undesirable consequences of intratumoral hypoxia.

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