Heterogeneity of leukemic cells with regard to daunorubicin accumulation and efflux: potential role in drug resistance
2000 (English)Licentiate thesis, comprehensive summary (Other academic)
Cellular resistance to chemotherapy is a major cause of treatment failure in acute myelocytic leukemia (AML) and other malignancies. Drug resistance is multifactorial; the most studied mechanism being multidrug resistance (MDR), mediated by the P-glycoprotein (PPG), a transmembrane transport protein with a pump function, encoded by the mdr 1 gene. MDR is characterised by cross resistance to a wide range of chemotherapeutics of natural origin e.g. anthracyclines, vinca alkaloids, epipodophyllotoxins and taxanes. The aim of the present study was to elucidate transport kinetics of the anthracycline daunorubicin (Dnr) and to study various forms of heterogeneity in cells from patients with AML. The ultimate goal is to improve treatment based on each patient's individual resistance patterns.
Density gradient isolated mononuclear cells from patients with AML were incubated with Dnr. Incubated cells were sorted on the basis of accumulation of the autofluorescent Dnr with flow cytometry. Gene expression of the Pgp and the multidrug resistance-associated protein (MRP) in sorted subpopulations were analysed with polymerase chain reaction (PCR). Drug accumulation and efflux in leukemic cell populations, apoptosis, expression of p53 and bcl-2 in the sorted subpopulations were studied with flow cytometry.
Gene expressions of mdrl and mrp were shown to be heterogeneous in the leukemic samples and drug accumulation correlated inversely to the gene expression. The blast cell population differed in drug accumulation and efflux compared to the total mononuclear cell population that contains also normal lymphocytes and monocytes. In leukemic samples with two blast cell populations the more immature blast cells accumulated less drug and had a higher efflux rate than the differentiating blast cells. Cell populations with higher drug accumulation entailed more apoptosis.
The results suggest that, since several resistance factors can occur in the same patient heterogeneity in the leukemic cell population ought to be taken into account whenever resistance patterns are studied.
Place, publisher, year, edition, pages
Linköping: Linköping University , 2000. , 41 p.
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 46
Drug resi stance. acute myeloid leukemia, flow cytometry, gene expression, transport kinetics, apoptosis
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-28317Local ID: 13449ISBN: 91-7219-580-0OAI: oai:DiVA.org:liu-28317DiVA: diva2:249123
2000-04-14, Lab ettans Sal1, Hälsouniversitetet, Linköping, 13:00 (Swedish)
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