Loading...
Projects / Programmes source: ARIS

The influence of active transport and patients' genotypes on the therapeutic outcome of chronic myeloic leukemia

Research activity

Code Science Field Subfield
3.04.00  Medical sciences  Oncology   

Code Science Field
B490  Biomedical sciences  Haematology, extracellular fluids 

Code Science Field
3.02  Medical and Health Sciences  Clinical medicine 
Keywords
Imatinib, chronic myeloic leukemia, therapy, active transport, genotyping.
Evaluation (rules)
source: COBISS
Researchers (23)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  25492  PhD Katja Berginc  Pharmacy  Researcher  2011 - 2012  77 
2.  15099  PhD Darko Černe  Pharmacy  Researcher  2012 - 2014  261 
3.  07012  PhD Peter Černelč  Microbiology and immunology  Researcher  2011 - 2014  479 
4.  17434  Mihaela Kolarev    Technical associate  2011 - 2014 
5.  30818  PhD Eva Kralj  Pharmacy  Junior researcher  2011 - 2013  18 
6.  11122  PhD Albin Kristl  Pharmacy  Head  2011 - 2014  350 
7.  35674  PhD Nejc Lamovšek  Administrative and organisational sciences  Technical associate  2013 - 2014  22 
8.  17430  Nevenka Lilik    Technical associate  2011 - 2014 
9.  12189  PhD Janja Marc  Metabolic and hormonal disorders  Researcher  2011 - 2014  711 
10.  33916  Anica Mihajlović    Technical associate  2011 - 2012 
11.  25809  PhD Vid Mlakar  Metabolic and hormonal disorders  Researcher  2013  96 
12.  18154  PhD Barbara Ostanek  Metabolic and hormonal disorders  Researcher  2011 - 2013  187 
13.  23818  PhD Tadej Pajič  Human reproduction  Researcher  2011 - 2014  178 
14.  12684  PhD Helena Podgornik  Microbiology and immunology  Researcher  2011 - 2014  346 
15.  23126  PhD Irena Preložnik Zupan  Oncology  Researcher  2011 - 2014  415 
16.  22657  PhD Irena Prodan Žitnik  Pharmacy  Researcher  2013 - 2014  48 
17.  35675  Urška Ribič    Technical associate  2013 - 2014 
18.  23549  PhD Robert Roškar  Pharmacy  Researcher  2011 - 2014  301 
19.  35951  Vanja Strbad    Technical associate  2013 - 2014 
20.  23420  PhD Jurij Trontelj  Pharmacy  Researcher  2011 - 2014  254 
21.  32306  PhD Janja Zupan  Metabolic and hormonal disorders  Researcher  2011 - 2012  110 
22.  22659  PhD Simon Žakelj  Pharmacy  Researcher  2011 - 2014  162 
23.  35673  Špela Žula    Technical associate  2013 - 2014 
Organisations (2)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0312  University Medical Centre Ljubljana  Ljubljana  5057272000  76,699 
2.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,536 
Abstract
Chronic myeloid leukaemia (CML) is a malignant neoplasm of hematopoietic stem cell and is classified among mieloproliferative diseases. 15-20% of adult patients with leukaemia have CML. The natural course of the disease lasts 3 – 5 years and has three phases: chronic, in which 85% of patients are diagnosed, followed by an accelerated period, leading to blast transformation. Since 2001, an era of molecular therapy of CML began with imatinib, the first tyrosine kinase inhibitor (TKI) on the market. Since then the eight-year survival of patients with CML is as high as 93% if only deaths related to CML are considered. Severe intolerance of imatinib occurs in less than 5% of patients while the primary resistance to treatment occurs in 25% of patients treated with imatinib. Several mechanisms of resistance exist and are intensely investigated. It seems that the resistance is either directly or indirectly (through increased emergence of TKI resistant clones) linked to insufficient drug concentration at the site of action. Such low concentrations, emergence of resistance and therapy failure were already linked to poor uptake of imatinib in the target cells by OCT1 transporters. The diffusion of imatinib from the gastrointestinal lumen to blood plasma, as well as its diffusion from blood plasma to target cells, are most likely highly dependent on transport protein activity. In the proposed project we wish to explore the processes that determine imatinib concentrations at the site of action – that is in the target cells (mononuclear leukocytes). Our main focus will be on the molecular mechanisms of drug absorption from the gastrointestinal tract into the bloodstream and, regarding the clinical significance, its distribution between the blood plasma and the cytosol of target cells in the peripheral blood and in bone marrow. Therefore we will develop a method for a direct measurement of imatinib and N-desmethyl imatinib concentrations in the target cells of peripheral blood and bone marrow. This method will also become a basis for individual determination of imatinib uptake into target cells of patients before and immediately after the beginning of therapy. Our aim, therefore, is to validate whether it is possible to determine imatinib and N-desmethyl imatinib concentrations in the blood cells with a highly sensitive LC-MS-MS analytical method and whether the method is applicable in the determination of active drug uptake in the peripheral blood mononuclear cells by OCT1 prior to therapy. By doing so we can provide a clinically useful method for individual determination of OCT1 activity in the target cells, which is important for the success of CML therapy with imatinib. The relationship between the polymorphisms of the selected genes and concentrations of imatinib and N-desmethyl imatinib in blood plasma as well as their intracellular concentrations will be investigated and the data will be correlated to the treatment outcomes in the population of Slovenian patients. The relationship between the expression of relevant genes for drug transporters and metabolic enzymes in the leucocytes from the bone marrow and those in the peripheral blood will also be evaluated. Specifically, we are interested in the expression of these genes in leucocytes from bone marrow and peripheral blood and its influence on the intracellular concentrations of imatinib and N-desmethyl imatinib. Finally, the expression of the above-mentioned genes will be followed during the therapy at several control time-points. This way, a correlation between the selected gene expression and effectiveness of the treatment can be established. We believe that the knowledge gained and the methods developed will contribute to the early determination of the optimum imatinib dose, or when necessary, the patient can be prescribed the second line agents, which do not depend on OCT1 activity, to achieve the treatment effectiveness as early as possible.
Significance for science
Imatinib transport mechanisms through mucosal barrier in GIT as well as into blood cells (imatinib uptake) were explored and investigated. We were so able to explain high bioavailability of large and basic imatinib molecule and its high variability of plasma concentrations among patients with active absorption and elimination. The methodology for analytical evaluation of intracellular drug concentration is rare and usually reliant upon the use of radioactively labeled drugs. For the purpose of this project we developed an appropriate LC-MS analytical method for imatinib determination in plasma and in blood cells. The method for the determination of imatinib concentration in granulocytes has not yet been published in the literature. Besides, (in the literature not yet known) analytical method for the simultaneous measurement of imatinib, nilotinib and dasatinib in dried blood spot by ultra high performance liquid chromatography tandem mass spectrometry was developed.
Significance for the country
We believe that the knowledge gained and the methods developed in this project will contribute to the early determination of the optimum imatinib dose, or when necessary, the patient can be prescribed the second line agents such as nilotinib and dasatinib, which are independent of OCT1 activity, to achieve the treatment effectiveness as early as possible.
Most important scientific results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
Views history
Favourite