Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients

Karas-Kuzelicki, Natasa; Jazbec, Janez; Milek, Miha; Mlinarič-Raščan, Irena

doi:10.1038/leu.2008.317

Cited by 42 publications

(31 citation statements)

References 5 publications

(9 reference statements)

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“…27 Patients with leukemia who are heterozygous for the TPMT variant were found to have an increased susceptibility to 6-mercaptopurine-related hematological toxic effects and needed reduced doses of the drug if they carried mutations in the MTHFR gene. 28 However, studies using azathioprine in the settings of transplantation and inflammatory bowel disease both showed that MTHFR genotype was not associated with an increased risk of toxicity during thiopurine treatment. 29,30 This finding could be a result of differences in the dosing needed to treat patients with leukemia.…”

Section: Azathioprine-related Myelosuppressionmentioning

confidence: 98%

Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Budhiraja

Popovtzer

2011

Nat Rev Nephrol

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Section: Azathioprine-related Myelosuppressionmentioning

confidence: 98%

Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Budhiraja

Popovtzer

2011

Nat Rev Nephrol

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“…In western researches, both thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variant alleles have been reported to influence the need for 6-MP dose reduction or therapy interruption during maintenance therapy. [1][2][3][4] TPMT variant alleles are rare in the Japanese population, and even patients with wild-type TPMT alleles have shown severe toxicities that require therapy interruption or 6-MP dose reduction in Japanese. We have previously reported that patients with low ITPA activity frequently required therapeutic dose reduction.…”

Section: Introductionmentioning

confidence: 99%

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

et al. 2014

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Multidrug resistance protein 4 (MRP4) is involved in the efflux of nucleoside derivatives and has a role in the determination of drug sensitivity. We investigated the relationship between MRP4 genetic polymorphisms and doses of the 6-mercaptopurine (6-MP) and methotrexate. Further, we evaluated the frequency of therapeutic interruption during maintenance therapy in Japanese children with acute lymphoblastic leukemia (ALL). Ninety-four patients received an initial 6-MP dose in the range of 30 − 50 mg m − 2 in this analysis. Patients with homozygous variant allele in any of MRP4 G2269A, C912A and G559T required high frequency of 6-MP dose reduction compared with non-homozygous individuals. Average 6-MP dose for patients with homozygous variant allele on either MRP4 or inosine triphosphate pyrophosphatase was significantly lower than that for patients with non-homozygous variant allele during maintenance therapy (30.5 versus 40.0 mg m − 2 , P = 0.024). Therefore, MRP4 genotyping may be useful for personalizing the therapeutic dose of 6-MP during the ALL maintenance therapy in Japanese.

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“…Importantly, TPMT genotype is a strong predictor for TPMT activity and even patients heterozygous for the TPMT loss-of-function alleles *2A or *3 showed significantly higher incidences of dose reductions due to toxicity [67,68]. Due to the substantial body of evidence that links TPMT genotype to thiopurine treatment outcomes and adverse events, TPMT genotyping is already widely applied in clinical practice [69,70].…”

Section: Associations Between Tpmt Genotype and Thiopurine Toxicitymentioning

confidence: 99%

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

Lauschke

Milani

Ingelman‐Sundberg

2017

AAPS J

109

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Abstract.Much of the inter-individual variability in drug efficacy and risk of adverse reactions is due to polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics or immunological responses. Pharmacogenetic research has identified a multitude of gene-drug response associations, which have resulted in genetically guided treatment and dosing decisions to yield a higher success rate of pharmacological treatment. The rapid technological developments for genetic analyses reveal that the number of genetic variants with importance for drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to millions of rare mutations. Here, we review the evolutionary background of genetic polymorphisms in drugmetabolizing enzymes, provide some important examples of current use of pharmacogenomic biomarkers, and give an update of germline and somatic genome biomarkers that are in use in drug development and clinical practice. We also discuss the current technology development with emphasis on complex genetic loci, review current initiatives for validation of pharmacogenomic biomarkers, and present scenarios for the future taking rare genetic variants into account for a true personalized genetically guided drug prescription. We conclude that pharmacogenomic information for patient stratification is of value to tailor optimized treatment regimens particularly in oncology. However, the routine use of pharmacogenomic biomarkers in clinical practice in other therapeutic areas is currently sparse and the prospects of its future implementation are being scrutinized by different international consortia.

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Heterozygosity at the TPMT gene locus, augmented by mutated MTHFR gene, predisposes to 6-MP related toxicities in childhood ALL patients

Cited by 42 publications

References 5 publications

Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Azathioprine-related myelosuppression in a patient homozygous for TPMT*3A

Multidrug resistance protein 4 (MRP4) polymorphisms impact the 6-mercaptopurine dose tolerance during maintenance therapy in Japanese childhood acute lymphoblastic leukemia

Pharmacogenomic Biomarkers for Improved Drug Therapy—Recent Progress and Future Developments

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