Thiopurine S-Methyltransferase (TPMT) Gene Polymorphism in Brazilian Children With Acute Lymphoblastic Leukemia: Association With Clinical and Laboratory Data

Silva, Marcilene Rezende; Oliveira, Benigna Maria de; Viana, Marcos Borato; Murao, Mitiko; Romanha, Álvaro J.

doi:10.1097/ftd.0b013e31818b0f31

Cited by 21 publications

(17 citation statements)

References 36 publications

(48 reference statements)

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“…Despite similar report from Silva et al (13) , three other studies (2,5,10) have obtained different results, where TPMT alleles *2 and *3C were most frequent. These differences may be related to variation of radical distribution among Brazilian regions.…”

Section: Discussioncontrasting

confidence: 43%

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Gastal¹,

Moreira²,

Noble

et al. 2012

Arq. Gastroenterol.

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-Context -The use of thiopurine drugs such as azathioprine and 6-mercaptopurine has become quite common in the treatment of inflammatory bowel disease, transplantation and acute leukemias. Despite their effectiveness, these drugs are capable of causing drug-induced toxicity with the risk of death by myelosuppression. It is now known that these complications occur because of genetic polymorphisms of the thiopurinemethyltransferase (TPMT) enzyme, responsible for its metabolism. Objective -To assess the prevalence of thiopurine methyltransferase polymorphisms in the population of Joinville, SC, Brazil. Methods -We analyzed the frequency of four main allelic variants of the TPMT gene in 199 blood donors from Joinville, from February to April 2010. Results -The normal allele ("wild-type") was found in 93.9% of subjects studied. TPMT variants were detected in 12 subjects (6.03%).Conclusions -From this study, it was estimated at 6% the risk of toxicity by the administration of azathioprine and 6-mercaptopurine to patients in Joinville.

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Section: Discussioncontrasting

confidence: 43%

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Gastal¹,

Moreira²,

Noble

et al. 2012

Arq. Gastroenterol.

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“…Several studies indicate that TPMT polymorphisms are associated with 6-MP toxicity or dosage [3,6,15-17]. To correlate our results with clinical findings we determined laboratory parameters and 6-MP dosage in ALL patients who completed the maintenance phase of the ALL treatment.…”

Section: Discussionmentioning

confidence: 98%

“…The frequency and distribution of TPMT alleles in Chile are similar to that of Hispanics in other Latin American countries. In fact, within the region, polymorphism prevalence differs only in Brazil [14,15], a finding explained by their unique racial mixture.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia

et al. 2014

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BackgroundMercaptopurine (6-MP) plays a pivotal role in treatment of childhood acute lymphoblastic leukemia (ALL); however, interindividual variability in toxicity of this drug due to genetic polymorphism in 6-MP metabolizing enzymes has been described. We determined the prevalence of the major genetic polymorphisms in 6-MP metabolizing enzymes in Chilean children with ALL.Methods103 Chilean pediatric patients with a confirmed diagnosis of ALL were enrolled. DNA was isolated from whole blood and genetic polymorphism in thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) coding genes were detected by polymorphism chain reaction-restriction fragment length (PCR-RFLP) assay.ResultsThe total frequency of variant TPMT alleles was 8%. TPMT*2, TPMT*3A and TPMT*3B alleles were found in 0%, 7%, and 1% of patients, respectively. For ITPA, the frequency of P32T allele was 3%. We did not observe any homozygous variant for TPMT and ITPA alleles. We also analyzed a subgroup of 40 patients who completed the maintenance phase of ALL treatment, and we found that patients carrying a TPMT gene variant allele required a significantly lower median cumulative dosage and median daily dosage of 6-MP than patients carrying wild type alleles.ConclusionTMPT genotyping appears an important tool to further optimize 6-MP treatment design in Chilean patients with ALL.

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“…Silva and colleagues evaluated the influence of TMTP variants on clinical and laboratory data in a group of children and adolescents with acute lymphoblastic leukemia [87]. TMTP *2, *3A and *3C alleles were not associated with sex, interval of 6-mercaptopurin dose, leukocytes count, and event-free survival ( Table 3).…”

Section: Phase II Drug Metabolizing Enzymes Tpmtmentioning

confidence: 97%

“…The frequencies of TPMT variants were investigated in healthy Brazilian individuals with different ethnic backgrounds, blood donors from the Southern region and leukemic children [85][86][87][88].…”

Section: Phase II Drug Metabolizing Enzymes Tpmtmentioning

confidence: 99%

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

Cerda

Hirata²,

Hirata³

2014

Drug Metabolism and Drug Interactions

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Phase I and II drug metabolizing enzymes (DMEs) play an important role in biotransformation of endogenous and exogenous compounds including drugs currently used in pharmacoterapy. Moreover, the genetic variability of DMEs causes important interindividual differences in drug and metabolite exposure, drug response, and risk of adverse drug reactions. We reviewed pharmacogenetics/pharmacogenomics (PGx) studies that evaluated the influence of polymorphisms in the CYPs genes - mainly CYP1, CYP2 and CYP3 gene families - and in the phase II genes - TPMT, NAT2, GSTs and UGTs - on therapeutic response in Brazilian cohorts. Ethnic admixture of Brazilians resulted in a population characterized by a unique genetic profile, in which ancestry informative markers change continuously among ethnic groups. Therefore, some of the PGx biomarkers have a different distribution among Brazilians and PGx data from well-defined ethnic groups are not applicable to Brazilian populations. PGx data focused on phase I and phase II DMEs from Brazilian studies are needed in order to establish the influence of the genetic diversity on therapeutic response to clinically relevant drugs in a population with a composition from a complex genetic admixture. These studies and their impact are discussed in this review.

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Thiopurine S-Methyltransferase (TPMT) Gene Polymorphism in Brazilian Children With Acute Lymphoblastic Leukemia: Association With Clinical and Laboratory Data

Cited by 21 publications

References 36 publications

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Toxicity of azathioprine: why and when? analysis of the prevalence of polymorphism in Joinville, SC, Brazil

Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia

Pharmacogenetics of drug metabolizing enzymes in Brazilian populations

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