Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy representing approximately 30% of all childhood malignancies and 80% of paediatric leukaemias (Rubnitz and Pui, 2003). The prognosis of this disease has dramatically improved with a 5 year survival of 90% (Pui et al., 2009).
A further increase in the survival rate will depend on a reduction in drug-related toxicity, resulting in less interruption of chemotherapy and fewer relapses of the disease (Kishi et al., 2007).
The purine antimetabolite 6-mercaptopurine (6-MP) is metabolized through three metabolic pathways: S-methylation to produce inactive 6-methylmercaptopurine catalyzed by thiopurine methyltransferase (TPMT); oxidation to 6-thiouric acid via xanthine oxidase; and formation of 6-thioinosine 50 monophosphate catalyzed by hypoxanthine phosphoribosyltransferase (McLeod et al., 2000).
The cytotoxic action of 6-MP is caused by incorporation of toxic
thioguanine nucleotides (TGN) into DNA chains, thus leading to
inhibition of replication and subsequent cellular degradation (Krynetski et al., 1996).
Thiopurine methyle transferase-encoding gene (TPMT) is located on the short arm of chromosome 6 (6p22.3); it consists of 10 exons and 9 introns, and contains 27 kbp. The highest TPMT activity is observed in wild-type homozygotes, that is, carriers of TPM 1 allele, while intermediate activity is found in heterozygotes, and no, or trace activity is seen in homozygotes with two variant alleles (Kurzawski et al., 2003).
An increased risk of adverse reactions to 6-MP is associated with the accumulation of TGN, which is inversely proportional to TPMT activity (Desire et al., 2010).
Individuals homozygous for variant TPMT alleles show 10- to 15-fold increases in the accumulation of toxic metabolites. However, a reduction in the standard dose to 5–10% in those individuals can achieve an antineoplastic effect, with partial or total loss of myelosuppression (Pogorzelski et al., 2011).
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