Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia

Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

“…Thiopurines are widely used to treat acute lymphoblastic leukemia (ALL) of childhood, inflammatory bowel disease, autoimmune diseases and organ transplant recipients (Paterson and Tidd, 1975;Lennard, 1992). These drugs, like many cytotoxic agents, have a relatively narrow therapeutic index, with the potential for life-threatening druginduced toxicity, primarily myelosuppression (Lennard et al, 1989;Evans et al, 1991;Lennard, 1992). Large inherited variations in human tissue TPMT enzyme activity -ranging from high to virtually undetectable levels of activity -were first described over two decades ago (Weinshilboum and Sladek, 1980) (Figure 1).…”

“…TPMT *3C, the most common functionally significant variant allele in East Asia (frequency approximately 2%), includes only the codon 240 SNP, and the rare TPMT *3B allele has only the codon 154 SNP (Figure 2) (Szumlanski et al, 1996). The presence of TPMT*3A and *3B result in a virtual lack of TPMT enzyme activity and protein in the tissues of subjects who carry these alleles and, as a result, patients homozygous for these alleles can suffer severe, life-threatening myelosuppression when treated with standard doses of thiopurines, that is, they are 'overdosed' on standard doses (Lennard et al, 1989(Lennard et al, , 1990Evans et al, 1991). The reason why altering only two amino acids out of 245 results in such a striking phenotype will be addressed subsequently.…”

“…Although the bulk of thiopurines are metabolized by xanthine oxidase (XO), variation in the methylation step is much greater than for XO-catalysed oxidation (Guerciolini et al, 1989;Krynetski and Evans, 2003) and, in hematopoietic tissue, the methylation pathway is critical because xanthine oxidase is not expressed in hematopoietic tissue (Lennard et al, 1987). A series of clinical studies have shown that level of RBC TPMT activity is inversely correlated with the level of RBC 6-TGN and, as a result, inherited decrease in the methylation step makes more drug available for the multistep pathway that leads to the formation of active metabolites, 6-TGNs (see Figure 3) -resulting in druginduced myelosuppression (Lennard et al, 1987(Lennard et al, , 1989(Lennard et al, , 1990Evans et al, 1991). Therefore, patients homozygous for alleles that result in low TPMT activity have elevated 6-TGNs when treated with standard doses of thiopurines and are at greatly increased risk for lifethreatening, drug-induced myelosuppression.…”

Pharmacogenomics: Challenges and Opportunities

“…A well-studied example that is entering routine clinical practice is the thiopurine methyltransferase (TPMT) gene, whose protein product is responsible for bioinactivation of thiopurines, such as azathioprine or mercaptopurine (1,16,17). Rare individuals who are homozygous for loss of function variants are at high risk for bone marrow aplasia during therapy with standard doses, and this is stated in the package label.…”

Clinical significance of polymorphism of thiopurine methyltransferase gene in children with acute lymphoblastic leukemia during programmed therapy

“…Генетический полиморфизм ТРМТ представляет собой наиболее частый вариант, влияющий на метаболизм так называемых тиопури-нов, включая 6-MP. Полиморфизм может приводить к значительному снижению активности фермента и повышению риска лейкопении, ассоциированной с лечением [23][24][25][26]. В настоящее время известно бо-лее 20 генетических вариантов с низкой функцио-нальной активностью ТРМТ, 2 из которых -ТРМТ*2…”