These cells appear to be highly malignant and within 21 days only 10,000 make it clear cells were needed to reproducibly cause terminal leukemia in all transplant recipients. Survival of the nilotinib treated animals was significantly longer and we conclude that nilotinib is also very effective thing against these highly malignant cells in vivo. However,in both the transplant model and the transgenic model,animals did die of leukemia after we stopped treat ment and the relapse was relatively rapid. There were also transplanted mice that developed leukemia while on treatment. Therefore,in these models,nilotinib did not provide a cure for P190 Bcr Abl caused ALL.

This result is of Inhibitors,Modulators,Libraries interest in the context of a phase I clinical trial that included 13 patients with Ph positive ALL,in which one patient showed a partial hemato logical response and one a complete molecular remission,indicating that the Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries drug was,overall,not highly effective in this type of leukemia. The question therefore remains why Ph positive Inhibitors,Modulators,Libraries ALL over all responds less well to Bcr Abl tyrosine kinase inhibitors including imatinib and nilotinib. Our results do not sup port the view that subclones harboring point mutations in the Abl kinase domain are rapidly selected out. Our stud ies do suggest that drug levels may be an important factor. We saw a clear inhibition of P190 Bcr Abl tyrosine kinase activity at 2 hours but not at 23 hours after the last treat ment with nilotinib,indicating that in these mice,the drug concentration in plasma at 23 hours was insufficient to fully inhibit the P190 Bcr Abl.

Weisberg et al meas ured plasma levels of nilotinib Inhibitors,Modulators,Libraries in mice and reported that at 75 mg kg,nilotinib concentrations of 29 and 2. 5M were present Inhibitors,Modulators,Libraries in their plasma at 2 and 24 hours. Kantarjian et al measured trough levels of nilotinib between 1 and 2. 3M nilotinib in humans. Our transgenic construct was generated using Inhibitors,Modulators,Libraries human BCR and ABL gene segments and will therefore encode a protein that is identical to the P190 Bcr Abl found in human Ph positive ALL. Thus,even with the highest dose of nilotinib,in humans,there is a period in which the levels approach those which were unable to fully inhibit the human P190 Bcr Abl protein in vivo in the mice.

We speculate,that Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries in the mice,a residual population of leukemic cells remains,and that over a 24 hour period,as the drug concentration starts Pazopanib FGFR to decrease during the later hours after administration,these residual resume prolifer ation. Over a period of time,this Inhibitors,Modulators,Libraries results in a slow increase in the http://www.selleckchem.com/products/Roscovitine.html tumor burden. Ex vivo,stroma was able to provide protection to these cells as well as the original parent cells when we treated them with a moderate 20 nM dose of nilotinib.