bioavailability of imatinib. Patients with low expression, activity or polymorphisms of OCT1 had significantly lower intracellular levels of imatinib. The response of patients with low OCT1 activity was significantly dose-dependent. This data indicates that OCT1 activity is an important determinant in the molecular response to imatinib. Alternative signaling pathway activation In a few patient groups, resistance may be caused by the activation of other signaling pathways, particularly the Src family kinases. The Src family kinases have been implicated in Bcr-Abl signaling and mediate imatinib resistance by stabilizing the active conformation of Bcr-Abl, a conformation that does not bind imatinib. Furthermore, increasing evidence suggests that Src family kinases are also involved in Bcr-Abl-independent forms of imatinib resistance. Solutions The treatment options for imatinib resistant or intolerant CML patients may include strategies such as increasing the dose of imatinib or the use of second-generation drugs. Escalation of imatinib-doses has shown to overcome some cases of primary resistance to imatinib, such as Bcr-Abl duplication, but the response is usually short acting. In the case of resistance or intolerance, it could be helpful to test for Bcr-Abl mutations to direct the choice of second line treatment as the variable options have different function profile against the different mechanisms of resistance. Second-generation drugs offer improved potency and a greater likelihood of success in resistant patients. There is also a growing interest in testing the hypothesis that administration of multiple Abl kinase inhibitors in early phase patients could be used to delay or prevent the emergence of drug resistant clones. The combination of two agents targeting different pathways involved in CML may significantly improve response rates and potentially increase survival. Second generation drugs Second generation drugs are intended to have decreased resistance and intolerance than imatinib. Second generation drugs that are currently marketed are nilotinib, dasatinib, bosutinib and ponatinib. Nilotinib (AMN107) Development Nilotinib is a phenylamino-pyrimidine derivative that is structurally related to imatinib. It was developed based on the structure of the Abl-imatinib complex to address the need associated with imatinib intolerance and resistance. Small changes were made on the imatinib molecule to make it more potent and selective as a Bcr-Abl inhibitor and these changes resulted in the discovery of nilotinib. Nilotinib is a selective Bcr-Abl kinase inhibitor. Nilotinib is 10-30 fold more potent than imatinib in inhibiting activity of the Bcr-Abl tyrosine kinase and proliferation of Bcr-Abl expressing cells. The drug effectively inhibits the