Grant: Project Grant

6-Mercaptopurine (6-MP) is used in combination with other drugs to treat acute lymphoblastic leukaemia (ALL). It is well known that not all patients respond to this drug to the same degree, with the therapeutic success rate declining with patient age. To be effective, 6-MP must gain access to the inside of the target leukemia cells. Therapeutic effectiveness as well as the severity of the 'off-target' side-effects of these drugs can thus be influenced by the activity of the 'transporters' in the cell membrane that 6-MP uses to get into the cells. Until recently, the identity of the transporters for 6-MP was unknown. This has now changed with the identification of a protein called ENBT1, encoded by the gene SLC43A3, which we propose to be the primary mechanism by which 6-MP gets into leukemia cells. We will determine how this novel protein transports 6-MP and assess other potential drug interactions. We will also use animal and isolated cell models to see whether blockade of this transport protein leads to reduced effectiveness of 6-MP and/or changes to its side-effect profile. We will also examine ways in which the number of these transporters can be increased in leukemia cells to make 6- MP even more effective. Finally, we will obtain blood and bone marrow samples from patients suffering from leukaemia and examine these for their level of SLC43A3 activity, and then correlate this information with the responsiveness of these patients to 6-MP. Understanding how this novel transport protein influences the therapeutic activity of 6-MP drugs will allow new clinical protocols to be developed to guide drug choice and enhance treatment of leukaemia.