Interindividual Variability in Tpmt Enzyme Activity: 10 Years of Experience with Thiopurine Pharmacogenetics and Therapeutic Drug Monitoring

Abstract

These results illustrate the usefulness of pharmacogenomics and metabolite measurement to improve the identification of noncompliance and patients at high risk for toxicity or therapeutic resistance. Original submitted 13 November 2013; Revision submitted 30 January 2014.

Tpmt Gene Expression is Increased During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia Patients in a TPMT Gene Promoter Variable Number of Tandem Repeat-Dependent Manner

“…The methylation of thiopurine drugs against their cytotoxicity potential is performed by the TPMT enzyme. It is well-established that thiopurine drugs' efficacy and toxicity correlates well with TPMT activity, which depends on TPMT gene variations [3].…”

“…In the clinical setting, the three most frequent variations in the TPMT coding region used as pharmacogenomic biomarkers are c.238 G > C, c.460 G > A and c.719 A > G. The latter is considered to be the most frequent genetic variant that leads to reduced TPMT activity. However, there is considerable individual variability regarding the enzyme activ-TPMT gene expression is increased during maintenance therapy in childhood acute lymphoblastic leukemia patients in a TPMT gene promoter variable number of tandem repeat-dependent manner ity among individuals who do not carry any TPMT coding region genetic variants [3,5]. Other factors that might be influencing TPMT enzyme activity include TPMT gene variations in its regulatory regions, age and gender of the patients, TPMT cofactor availability (S-adenosyl methionine), coadministration of other drugs that could potentially interfere with TPMT activity (e.g., methotrexate) as well as the life span of red blood cells.…”

Clinical implications of neuropharmacogenetics

“…Thiopurine S-methyltransferase (TPMT), the enzyme catalysing S-methylation of AZA, has a genetic polymorphism in 10% of Caucasians, with 1/300 individuals having complete deficiency. Patients with intermediate or deficient TPMT activity are at higher risk of toxicity after receiving standard doses of AZA, and a recent retrospective study of 7,360 patients referred for TPMT phenotype/genotype determination in France has confirmed a strong genotype-phenotype correlation and illustrates the usefulness of pharmacogenetics in clinical practice [106]. TPMT testing is recommended by the FDA to identify patients who are at increased risk of myelotoxicity and recommendations have been published to adapt the starting doses of AZA [107].…”

Whole exome sequencing detects variants of genes that mediate response to anticancer drugs

“…Of the genes responsible for the metabolism and transport of anticancer drugs using the WES data, we focused on the genes encoding cytochrome P450 isoforms (CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6) (Bell et al, 2015;Chen and Goldstein, 2009;Crews et al, 2012;Jin et al, 2005;Kim et al, 2004;Kiyotani et al, 2013;Takimoto et al, 2013;Tamaki et al, 2011;Xie et al, 2003), thiopurine methyltransferase (TPMT) (Chouchana et al, 2014), N-acetyltransferase 2 (NAT2) (Sim et al, 2014), UDP glucuronosyl transferase family 1 member A1 (UGT1A1) (Cheng et al, 2014;Sugatani, 2013), catechol-O-methyltransferase (COMT) (Zubieta et al, 2003), ATP-binding cassette subfamily B member 1 (ABCB1) (Bell et al, 2015;Frederiks et al, 2015), and cytidine deaminase (CDA) (Sugiyama et al, 2007(Sugiyama et al, , 2009, in the present study (Table 2) because the variants of these genes were previously described to affect drug response in Japanese populations (Kurose et al, 2012).…”