6-Mercaptopurine: Efficacy and Bone Marrow Toxicity in Childhood Acute Lymphoblastic Leukemia

Oral administration of 6-mercaptopurine (6MP), in combination with methotrexate, is applied for many years in the treatment of childhood acute lymphoblastic leukaemia (ALL) and these drugs are the cornerstones of maintenance treatment of this disease. 6MP is a pro-drug, and has to be converted by the anabolic purine pathway into active thiopurine nucleotides before excerting cytotoxicity. The initial step in the anabolic pathway is the conversion of 6MP into 6-thioIMP by the purine salvage enzyme HGPRT with PRPP as essential co-substrate. Subsequent conversion of 6-thioIMP leads to 6-thioguanine nucleotides from which 6-thio-deoxyGTP is incorporated into DNA. This incorporation of 6-thio-deoxyGTP into DNA appears to be the main contribution of the efficacy of 6MP. Another important metabolic route is the conversion of 6MP and its thiometabolites into 6-methylthiopurines, catalysed by the enzyme thiopurine methyltransferase (TPMT) with s-adenosylmethionine as essential co-substrate. In this paper, relations will be presented between thiopurine and methylthiopurine conversions of 6MP and the efficacy of 6MP in the treatment of childhood ALL and the systemic toxicity, which may be caused by this treatment.