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Printable Handouts
Navigable Slide Index
- Introduction
- Introduction (2)
- MP metabolism in hematopoietic tissues
- Azathioprine metabolism
- TPMT methylates (inactivates) 6MP
- Genetic polymorphism and drug metabolism
- 6MP and TG metabolism
- How does MP exert its antileukemic effects?
- MP kills leukemia cells by TG DNA incorporation
- TG incorporation causes modifications of DNA
- Schematic figure of TG
- Thioguanine alters the topoisomerase II function
- Thioguanine incorporation alters RNaseH function
- Mismatch repair enzymes and TG cytotoxicity
- Mismatch repair mode of action and apoptosis
- MeTIMP inhibits DNPS
- In-vivo studies of DNPS inhibition and cytotoxicity
- Multiple mechanisms for MP cytotoxicity
- Why is TPMT polymorphism important for MP?
- Absence of TPMT increases TGN production
- TPMT activity vs. 6-TGN levels
- Human red blood cell TPMP polymorphism
- TPMT genetic polymorphism and 6MP metabolism
- Inheritance of TPMT activity
- Mutant TPMT allele causes protein instability
- Deficient TPMT activity due to protein degradation
- PCR based genotypic method (1)
- PCR based genotypic method (2)
- Human TPMT gene and mutant alleles
- High concordance of genotype and phenotype
- TPMT alleles of African-Americans, Caucasians
- TPMT variant alleles in various world populations
- TPMT non-functional mutant alleles
- Rare TPMT alleles
- Importance of TPMT haplotype for common SNPs
- Additional approaches for TPMT allele identification
- Drug exposure determined by TPMT genotype
- Toxicity determined by TPMT genotype
- TPMT genotype and tolerance of azathioprine
- TPMT genotype in thiopurine intolerant patients
- TPMT genotype and 6MP dose requirement
- 6MP dose reduction in TPMT deficient patients
- Fatal toxicity from AZA in a TPMT-deficient patient
- Dosing 6MP with and without pharmacogenetics
- Dose reduction did not influence on relapse
- TPMT-KO mouse recapitulates TPMT phenotypes
- Interactions may result in adverse effects
- Brain tumors in patients receiving 6MP + radiation
- Possible molecular mechanism for the high risk
- TPMT and ITPA exhibit genetic polymorphism
- ITPA genotype and 6MP metabolites
- Inactive TPMT and inactive ITPA
- ITPA and TPMT genotypes and 6MP metabolites
- ITPA and TPMT genotypes and toxicity
- Potential of pharmacogenomics
- The future of diagnostics in pharmacogenomics
- Acknowledgements
Topics Covered
- Pharmacogenomics to optimize cancer chemotherapeutics
- The genetic polymorphism of thiopurine methyltransferase (TPMT)
- Its influence on thiopurine (e.g., mercaptopurine, azathioprine) therapy
- Molecular and biochemical basis of this pharmacogenetic trait
- Clinical diagnostic widely used to individualize and optimize thiopurine therapy for cancer and other diseases
- Update talk: Hematologic toxicity of thiopurines
- Update talk: TPMT
- Update talk: NUDT15
- Update talk: Ancestry-related differences in allele frequency
Links
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External Links
Talk Citation
Evans, W. (2022, August 30). Genetic polymorphism of thiopurine methyltransferase and thiopurine therapy: from molecular genetics to clinical medicine [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 9, 2024, from https://doi.org/10.69645/DNFC6499.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. William Evans has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Update Available
The speaker addresses developments since the publication of the original talk. We recommend listening to the associated update as well as the lecture.
- Full lecture Duration: 55:09 min
- Update Interview Duration: 6:51 min
- Update Duration: 9:26 min
Genetic polymorphism of thiopurine methyltransferase and thiopurine therapy: from molecular genetics to clinical medicine
A selection of talks on Oncology
Transcript
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0:04
This lecture focuses on the genetic polymorphism of human thiopurine methyltransferase,
and the influence these genetic polymorphisms have on thiopurine therapy,
and the lecture will span from molecular genetics to
the clinical application of these diagnostics
in prescribing and individualizing therapy with thiopurines.
Thiopurines include azathioprine, which is a prodrug for mercaptopurine,
as well as mercaptopurine,
a widely used antileukemic agent, and 6-thioguanine,
which is also affected by this polymorphism,
although perhaps less dramatically.
Each of these medications is inactivated through
methylation by this polymorphic thiopurine methyltransferase enzyme,
and it's been shown that individuals who
inherit low activity of thiopurine methyltransferase
have an increased risk of toxicity if
treated with the conventional doses of mercaptopurine,and azothioprine
and to some extent thioguanine.
1:17
This slide depicts the metabolism of mercaptopurine,
abbreviated MP in this slide,
which indicates that this medications either activate it to thioguanine nucleotides,
abbreviated TGN, by a multi enzymatic process,
the first step of which is catalyzed by the enzyme HPRT,
or this medication is inactivated either by methylation catalyzed by TPMT,
or by the enzyme xanthine oxidase.
Both of those enzymes convert mercaptopurine to
inactive metabolites that cannot be further activated.
In many tissues, the inactivation is controlled by both xanthine oxidase and TPMT,
but in hematopoietic tissues,
xanthine oxidase activity is very low, if at all,
meaning that the inactivation is determined by TPMT,
and the activation is determined by HPRT.
In that case, you would predict that patients who lack
TPMT activity would not inactivate the drug as well,
and they would shunt more drug down the activation pathway and
accumulate more of the active thioguanine nucleotide metabolites.
This slide depicts the same metabolic pathway as on the previous slide,
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