survival of cells resistant Bcr Abl positive imatinib. PI3K mTOR can be activated by treatment with imatinib in vitro and in vivo. PI3K activation has been found that a key role in the survival of the cell w During the early initiation of treatment with imatinib ne before the onset of mutations in Pelitinib EKB-569 the kinase Dom, a kr Ftigen what resistance. This effect can be effectively inhibited by pharmacological inhibition of mTOR or AKT siRNA treatment specifically c in vitro. Recently, an r Potential for autocrine secretion of GM-CSF as a mechanism against Bcr-Abl positive regulatory cells resist imatinib and nilotinib were reported. Drogenabh-Dependent cellular Ren resistance EFFL ux pumps or interception of drug binding proteins Have been proposed to cause lower intracellular Re levels of imatinib.
An increase in the serum A1AGP what a decrease in the bioavailability of LY2228820 imatinib has been proposed as a mechanism of resistance. R The Liaison A1AGPimatinib and distribution as well as reduced blood imatinib resistance is controversial. In vitro experiments with explosions A1AGP patients showed that at concentrations observed in patients to reduce the concentration of imatinib almost 10th However, there is no correlation between high A1AGP with imatinib resistance, despite the fact that almost 50 CML patients have an h A1AGP here. Drug transporters play an r Important in the regulated transport of drugs across the cell membrane and thus the determination of the bioavailability of the drug and the intracellular Higher concentrations of active ingredients.
It became clear that transport proteins essential for cellular Ren recording and EFFL ux of imatinib: In vitro experiments have shown that Leuk miezellen of imatinib absorption strongly depends on the temperature ngig best tigende one active transport process. Imatinib is a substrate for human organic cation transporter 1, but not or hOCT2 hOCT3. Imatinib clearance at st strongest With P-glycoprotein multidrug resistance transporter of the multi-drug resistance gene 1, also known as ABCB1 and breast cancer resistance protein BCRP associated known. Interestingly, imatinib both a substrate and an inhibitor of BCRP. Therefore, BCRP-mediated resistance to imatinib is attenuated is Cht by imatinib-induced reduction of BCRP expression.
Strategies for overcoming resistance Gain deeper Ndnis why transient responses and completely’s Full resistance to imatinib was an opportunity strategies that develop in a position to overcome the resistance. To go Ren increase the dose of imatinib imatinib combination with other agents, and novel inhibitors of BCR-ABL. BCR-ABL inhibitors new extended knowledge of the various mechanisms of resistance to imatinib significantly aid in the development of new tyrosine kinase inhibitors. One of the aims was to compounds to identify the bind and inhibit Abl kinase, however, are less affected by bcrabl point mutations. In particular, analysis of the crystal structure of Abl imatinib for identifi cation of potential critical residues that interfere with the interaction of imatinib with mutated Bcr Abl were useful. Nilotinib Nilotinib