Projects / Programmes
Thiopurine pharmacogenetics
- novel diagnostics and individualized therapy
| Code |
Science |
Field |
Subfield |
| 3.04.00 |
Medical sciences |
Oncology |
|
| Code |
Science |
Field |
| B200 |
Biomedical sciences |
Cytology, oncology, cancerology |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| B790 |
Biomedical sciences |
Clinical genetics |
individualization of therapy, novel diagnostic, pharmacogeetics, toxicity, side effects
Researchers (16)
Organisations (3)
Abstract
Pharmacogenomics is the study of how an individual’s genetic inheritance affects the body’s responses to drugs. The application of pharmacogenomics in the individualized drug therapy offers the potential to improve drug effectiveness, reduce adverse side effects, and provide cost-effective pharmaceutical care. Objective of the proposed project encompasses from a bench to bedside concept, emphasizing the need of basic research application in the current clinical practice. The project will be conducted by an interdisciplinary team including a pediatric oncologist, molecular geneticist and a clinical biochemist and will provide novel concepts for application in the clinic as well as the importance of linking the first-hand clinical experiences to problem-solving oriented research.Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) and thioguanine (6-TG)] have a well-established role in the treatment of haematological neoplasia, and as immunosuppressive agents in a variety of chronic inflammatory conditions, as well as transplant rejection. An understanding of the competing pathways involved in the metabolism of thiopurines has important implications for predicting some of the more severe toxicity observed with these drugs. Thiopurine S-methyltransferase (TPMT) is an enzyme catalysing the S-methylation of 6-MP, thereby competing with xanthine oxidase (XO) and hypoxanthine guanine phosphoribosyl transferase (HGPRT) and limiting the amount of 6-MP metabolised to thioguanine nucleotides responsible for cytotoxic effects. Our own research results show that allelic polymorphisms in the TPMT gene predict the activity of the enzyme such that 1 in 10 of the population are heterozygous and have approximately 50% decreased activity of the metabolizing enzyme, whilst 1 in 300 are completely deficient. These individuals are at high risk of developing severe myelosupresion. We aim to obtain three levels of knowledge and implement them in the daily clinical practice: (1) Genetic characterization of the patient’s drug profile. Application of the diagnostics based on TPMT polymorphisms and HPLC enzyme activity analysis, developed in our laboratory.(2) Establishment of novel diagnostic tests by the identification and characterization of other candidate genes, or by using a genome scale non-candidate approach.(3) Understanding of the molecular mode of action of thiopurines and the metabolism of key enzymes.Proposed study will contribute to the further development of pharmacogenomics at the Faculty of Pharmacy, a field of study that combines the knowledge emerging from the Human Genome Project with classical pharmaceutical disciplines. By implementing the proposed project we also contribute to a common European research area and mobility of researchers.
