[Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia].
OBJECTIVE
For the purpose of clarifying the influence of thiopurine methyltransferase (TPMT) gene single nucleotide polymorphisms (SNPs) on the efficacy of thiopurines and risk for its toxicity and therefore improving the safety and efficacy of thiopurines, the authors investigated TPMT genotype in acute leukemia in children who were intolerant to the treatment with 6-mercap topurine (6-MP).


METHODS
TPMT genotype was determined in an unrelated population of 250 Chinese healthy blood donors and 280 children with acute leukemia. TPMT genotyping assay was based on polymerase chain reaction (PCR), restriction digestion of PCR products, denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing in the TPMT * 2 (G238C), TPMT * 3A (G460A, A719G) and TPMT * 3C (A719G).


RESULTS
There were 10 TPMT * 1/TPMT * 3C heterozygotes in 280 children. The frequency of the polymorphism was 3.6%. All the involved alleles were TPMT * 3C. Of the 160 children acute leukemia evaluated, 45 (26%) were intolerant to 6-MP. Presentations included hepatotoxicity and hematological toxicity. Six out of 45 children were heterozygous, while the other 39 were wild type homozygous. Before dosage adjustments for thiopurine, the hematologic toxicity and hepatotoxicity in TPMT heterozygous individuals occurred more frequently than in homozygous. Therefore, cases of TPMT heterozygotes experienced more missed doses of 6-MP.


CONCLUSIONS
TPMT genotype is associated with tolerance in acute leukemia in children. The heterozygote individuals have low TPMT activity. Therefore the frequencies of hemtopoietic toxicity and hepatoxicity are high after using 6-MP. Detection of SNPs in the TPMT genes is useful in identifying children before administration of 6-MP.
Ma
Xiao-li
XL
Hematology center Beijing Children's Hospital, Capital University of Medical sciences, Beijing 100045, China.
Zhu
Ping
P
Wu
Min-yuan
MY
Li
Zhi-gang
ZG
Hu
Ya-mei
YM
D000208:Acute Disease; D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use*; D008780:Methyltransferases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase