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In vitro chemosensitivity testing of selected myeloid cells in acute myeloid leukemia 
Karolinska Institutet.
Örebro University, Department of Nursing and Caring Sciences.
Karolinska Institutet.
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2003 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 44, no 5, p. 783-789Article in journal (Refereed) Published
Abstract [en]

In several studies different chemosensitivity assays have been examined in acute myeloid leukemia (AML). Some have shown that in vitro chemosensitivity testing is an independent prognostic factor but so far no one has been able to show that the use of these methods can improve treatment outcome. In an attempt to improve in vitro chemosensitivity testing in AML we wanted to establish and evaluate a new flow cytometry chemosensitivity assay. After 4 days of incubation viable mononuclear myeloid cells were identified by the exclusion of propidium iodide in CD13 or CD33 positive cells. Sixty-eight samples from 64 AML patients were included. In this study, we showed that the flow cytometry method is feasible in AML and we also found some correlations to clinical data. The secondary AML at diagnosis showed an in vitro resistance to etoposide and amsacrine that was significantly higher compared to de novo AML at diagnosis (p = 0.04 and p = 0.02). When AML patients at diagnosis were compared to resistant disease/relapse patients there was a significantly higher effect of ara-C in the diagnosis group (p = 0.03). Responders and non-responders were compared in vitro but we found no significant differences. In vitro mitoxantrone was more effective in multidrug resistance (MDR) negative cells compared to MDR positive cells (p < 0.01). This new method is feasible and makes it possible to selectively evaluate the effect of cytotoxic drugs in myeloid cells. Further studies with a larger group of patients are needed to evaluate the predictive value of the assay.

Place, publisher, year, edition, pages
Taylor & Frances healthsciences , 2003. Vol. 44, no 5, p. 783-789
Keyword [en]
Chemosensitivity, cytotoxicity, drug resistance, flow cytometry, acute myeloid leukemia
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-10578DOI: 10.1080/1042819031000067594PubMedID: 12802914OAI: oai:DiVA.org:oru-10578DiVA, id: diva2:317290
Available from: 2010-05-03 Created: 2010-05-03 Last updated: 2017-12-12Bibliographically approved
In thesis
1. On mechanisms of drug resistance in acute myeloid leukemia
Open this publication in new window or tab >>On mechanisms of drug resistance in acute myeloid leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis focus has been to increase the knowledge and understanding of some of the mechanisms responsible for drug resistance in acute myeloid leukemia, as well as identify possibilities to predict drug resistance at diagnosis.

We have studied the intracellular behavior of cytostatic drugs and their main metabolites (paper I) and the cellular response to cytostatic drugs (paper III). A new flow cytometry in vitro chemosensitivity assay was developed, to enable identification of viable myeloid cells and determination of drug sensitivity (paper II). Finally, possible new markers involved in drug resistance were investigated (paper IV).

In conclusion we found that idarubicin and daunorubicin are equally toxic at the same intracellular concentrations. The contribution of the main metabolites to the cytotoxic effects of idarubicin and daunorubicin, in both drug sensitive and drug resistant human myeloid leukemia cells, is low. It is most likely the pharmacokinetic properties of idarubicin and daunorubicin that confer their main cytotoxic effect. With the new flow cytometry chemosensitivity assay we selectively identified viable CD13/CD33 expressing myeloid cells and found that the cytotoxicity results correlated to clinical parameters, such as secondary AML and resistant disease. Short-term exposure of leukemia cell lines with different levels of drug resistance to ara-C revealed that Pgp mRNA and protein ex-pression levels, as well as GSTπ mRNA levels, were rapidly up-regulated. Clinically, this up-regulation may be of importance for the sequential scheduling of daunorubicin and ara-C during the induction treatment of AML. CRIM1 has

never been studied in the context of drug resistance before. We show for the first time that baseline expression of CRIM1 mRNA is much higher in drug resistant leukemia cells compared to drug sensitive cells. We also found a co-variance between CRIM1 and Pgp mRNA expression levels in leukemia cell lines with different levels of drug resistance, suggesting that CRIM1 may be useful as a marker of drug resistance.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2010. p. 87
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 45
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-10603 (URN)978-01-7668-729-1 (ISBN)
Public defence
2010-06-04, Wilandersalen, Universitetssjukhuset, Örebro, 15:54 (Swedish)
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Available from: 2010-05-05 Created: 2010-05-04 Last updated: 2017-10-18Bibliographically approved

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Prenkert, MalinTidefelt, Ulf

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