Nucleotide Metabolism: Mode of Action of Thiopurines in Leukemia

Thiopurines are active in a variety of lymphoid and myeloid leukemia and represent an important component of the systemic treatment of these malignancies1-4. Oral 6-mercaptopurine (6MP) in combination with methotrexate (MTX) forms the cornerstone of the maintenance therapy of children with acute lymphoblastic leukemia (ALL)4 and thioguanine (6TG) is used in regiments of acute myeloblastic leukemia and several other malignancies5, 6. The enhanced efficacy of combination of 6MP and MTX on survival of children with acute lymphoblastic leukemia has been empirically demonstrated. However, absorption of 6MP after oral dose is incomplete and variable7 and very little is known about the distribution or clearance of the metabolites of these drugs, and about the optimal concentration and duration of exposure required for cytotoxicity in vivo.