Projects / Programmes source: ARIS

Thiopurine pharmacogenetics - novel diagnostics and individualized therapy

Research activity

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
Evaluation (rules)
source: COBISS
Researchers (16)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  15104  PhD Saša Baumgartner  Pharmacy  Researcher  2006  306 
2.  26227  Manja Cedilnik    Technical associate  2005 - 2008 
3.  26498  PhD Teja Čelhar  Pharmacy  Junior researcher  2007 - 2008  38 
4.  29772  PhD Jana Dragojevič  Pharmacy  Researcher  2008  15 
5.  22621  PhD Polonca Ferk  Metabolic and hormonal disorders  Researcher  2007  140 
6.  00814  PhD Ksenija Geršak  Human reproduction  Researcher  2007 - 2008  522 
7.  15706  PhD Tanja Gmeiner  Pharmacy  Researcher  2007 - 2008  146 
8.  10972  PhD Janez Jazbec  Oncology  Researcher  2005 - 2008  314 
9.  01302  PhD Matjaž Jeras  Biotechnology  Researcher  2005 - 2008  358 
10.  21459  PhD Nataša Karas Kuželički  Pharmacy  Researcher  2005 - 2008  169 
11.  25491  PhD Miha Milek  Biochemistry and molecular biology  Junior researcher  2007 - 2008  58 
12.  18996  PhD Barbara Mlinar  Pharmacy  Researcher  2008  48 
13.  12443  PhD Irena Mlinarič Raščan  Pharmacy  Head  2005 - 2008  528 
14.  18154  PhD Barbara Ostanek  Metabolic and hormonal disorders  Researcher  2006  186 
15.  19786  Majda Sirnik    Technical associate  2006 
16.  29982  PhD Alenka Šmid  Pharmacy  Researcher  2008  121 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0311  Blood Transfusion Centre of Slovenia  Ljubljana  5053960  1,747 
2.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  75,648 
3.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,167 
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.
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