Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects

Brouwer, C.; Abreu, Ronney A. De; Keizer-Garritsen, Jenneke J.; Lambooy, Lambert H.J.; Ament, Kai; Riet, P. G. J. H. Ter; Wering, E. R. Van; Trijbels, Frans J.M.; Veerman, A. J. P.; Hoogerbrugge, Peter M.; Bökkerink, J.P.M.

doi:10.1016/j.ejca.2004.10.027

Cited by 41 publications

(35 citation statements)

References 29 publications

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“…Whether or not the TPMT activity indeed relates to age remains to be clarified [5,20,30,31]. Brouwer et al recently demonstrated that children with other diseases show higher TPMT activities than leucemic children [32]. They also observed lower activities before antileucemic treatment compared with those measured thereafter.…”

Section: Discussionmentioning

confidence: 97%

Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes

Khalil¹,

Erb²,

Khalil³

et al. 2005

Journal of Chromatography B

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Section: Discussionmentioning

confidence: 97%

Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes

Khalil¹,

Erb²,

Khalil³

et al. 2005

Journal of Chromatography B

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“…Previous studies of TPMT mutation incidence in several larger populations have not shown any prevalence among different age groups. 42,43 This was expected because TPMT polymorphisms are inborn mutations transmitted in an autosomalcodominant way. 44 Comparison of TPMT allele frequencies in the population of Serbia and Montenegro with the ethnic groups of similar origin and geographic settlement revealed that it was not statistically different (P .…”

Section: Discussionmentioning

confidence: 97%

Analysis of Thiopurine S-methyltransferase Polymorphism in the Population of Serbia and Montenegro and Mercaptopurine Therapy Tolerance in Childhood Acute Lymphoblastic Leukemia

Dokmanović

Urosevic²,

Janić³

et al. 2006

Therapeutic Drug Monitoring

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Thiopurine S-methyltransferase (TPMT) is an enzyme that converts thiopurine drugs into inactive metabolites. It is now well established that interindividual variation in sensitivity to thiopurines can be the result of the presence of genetic polymorphisms in the TPMT gene. The aim of this study was to determine the frequency and type of TPMT polymorphisms in the population of Serbia and Montenegro and to assess its relevance in the management of childhood acute lymphoblastic leukemia (ALL). Blood samples from 100 healthy adults and 100 children with ALL were analyzed for common mutations in the TPMT gene using polymerase chain reaction-based assays. The results revealed that allelic frequencies were 0.2% for TPMT*2, 3.2% for TPMT*3A, and 0.5% for TPMT*3B. A rare TPMT*3B allele was detected in 2 families. No TPMT*3C allele was found. The general pattern of TPMT-variant allele distribution as well as their frequencies in the population of Serbia and Montenegro, is similar to those determined for other Slavic and Mediterranean populations. The ability to tolerate 6-mercaptopurine (6-MP) -based maintenance therapy was used as a surrogate marker of hematologic toxicity. In the study of 50 patients with childhood ALL treated according to the BFM-like protocol, it was found that even TPMT-heterozygous patients are at greater risk of thiopurine drug-related leukopenia (mean duration of period when children missed therapy as a result of leukopenia for TPMT-heterozygous patients was 11.3 weeks vs 3.4 weeks for wild-type genotype patients, P < 0.01). In another group of 50 patients, the TPMT genotype was determined prospectively. The therapy protocol was modified considering their TPMT genotype. Administering reduced 6-MP dosages in the initial phase of maintenance allowed TPMT-heterozygous patients to later receive full protocol doses of both 6-MP and nonthiopurine therapy without omitting therapy resulting from myelotoxicity. These results justify performing TPMT genotyping before initiating thiopurine therapy in all children with ALL to minimize consequent toxicity.

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“…However, other drugs could affect TPMT enzyme activity although it is difficult to say what impact these drugs may have on the enzyme activity compared to the RBC age. Also, RBC transfusion may have an impact on the TPMT activity, although Brouwer et al, (2005) showed that this effect was not significant for wild type individuals receiving transfusions [15]. Determining…”

Section: Discussionmentioning

confidence: 99%

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

Wennerstrand

Mårtensson

Söderhäll

et al. 2013

Eur J Clin Pharmacol

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METHODSFifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before and 66 hours after start of high-dose MTX infusions. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukemic cell line. RESULTSForty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity compared to genotype at the time of diagnosis. TPMT decreased significantly 66 hours after the start of high-dose MTX infusions (-9.2 per cent, p=0.013). MTX bound to recombinant TPMT protein and inhibited the TPMT enzyme to a remaining activity of 16 percent. CONCLUSIONSThis study shows that TPMT genotyping should be preferred in children with ALL, since 40per cent of TPMT wild-type children are at risk of initial under-dosing of 6-MP in cases where 3 only TPMT enzyme activity is determined. MTX inhibits the TPMT enzyme activity after high-dose MTX infusions due to protein binding.

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Thiopurine methyltransferase in acute lymphoblastic leukaemia: biochemical and molecular biological aspects

Cited by 41 publications

References 29 publications

Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes

Interference free and simplyfied liquid chromatography-based determination of thiopurine S-methyltransferase activity in erythrocytes

Analysis of Thiopurine S-methyltransferase Polymorphism in the Population of Serbia and Montenegro and Mercaptopurine Therapy Tolerance in Childhood Acute Lymphoblastic Leukemia

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

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