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Imatinib activity in vitro in tumor cells from patients with chronic myeloid leukemia in chronic phase and blast crisis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Hematologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Hematologi)
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2006 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 17, no 6, 631-639 p.Article in journal (Refereed) Published
Abstract [en]

The aims of this study were to evaluate the feasibility of using the non-clonogenic fluorometric microculture cytotoxicity assay in drug sensitivity testing of tumor cells from patients with chronic myeloid leukemia. In nine samples (six chronic phase, three blast crisis), the drug sensitivities in tumor cells from blood versus from bone marrow and fresh tumor cells versus cryopreserved were compared. In 26 samples obtained in chronic phase (pretreatment), in six samples from patients in blast crisis and in the K 562 cell line, the activity of imatinib alone and in combination with cytarabine, vincristine, daunorubicin, interferon, arsenic trioxide and homoharringtonine was evaluated. All chronic myeloid leukemia chronic phase samples were sensitive to imatinib, with a mean IC50 at 10.3 mumol/l. The chronic myeloid leukemia samples from blast crisis (n=6) were significantly more sensitive to imatinib than the samples from chronic phase (n=26) (P<0.05), with an IC50 mean at 0.4 mumol/l. In blast crisis samples, significant positive interaction effects were observed between imatinib and all other tested drugs except for interferon. In chronic phase samples, interferon, daunorubicin and arsenic trioxide were the drugs with the highest frequency of positive interactions with imatinib (P<0.05). We conclude that the fluorometric microculture cytotoxicity assay may be a useful method for drug sensitivity testing in chronic myeloid leukemia patient samples from both chronic phase and blast crisis, and that testing primary tumor cells may have advantages over cell line studies. Imatinib shows a higher in vitro activity and more positive drug interactions in cells from blast crisis than chronic phase chronic myeloid leukemia patients. Combinations between imatinib and interferon, daunorubicin and arsenic trioxide may be interesting for future clinical trials in patients with chronic myeloid leukemia chronic phase.

Place, publisher, year, edition, pages
2006. Vol. 17, no 6, 631-639 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95821DOI: 10.1097/01.cad.0000217423.59831.dbPubMedID: 16917208OAI: oai:DiVA.org:uu-95821DiVA: diva2:170170
Available from: 2007-04-25 Created: 2007-04-25 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Clinical and Experimental Studies in Chronic Myeloid Leukemia: Studies of Treatment Outcome, In Vitro Cellular Drug Resistance and Gene Expression
Open this publication in new window or tab >>Clinical and Experimental Studies in Chronic Myeloid Leukemia: Studies of Treatment Outcome, In Vitro Cellular Drug Resistance and Gene Expression
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of the studies described in the thesis were to investigate different treatment strategies in chronic myeloid leukemia (CML) patients. Furthermore, activity of imatinib was investigated by in vitro cytotoxicity assay, and the gene expression pattern in interferon treated patients.

In a randomized prospective national study, we examined the influence of busulphan (n=89) versus hydroxyurea (n=90) treatment on time to blast crisis, and survival. There was no significant difference in survival between hydroxyurea and busulphan treated patients; median survival was 3.5 and 3.2 years, respectively. The 26 patients who underwent allogeneic stem cell transplantation had a significantly longer median survival (4.7 years) than those who were not transplanted.

We investigated the feasibility of mobilizing Philadelphia chromosome negative blood stem cells with intensive chemotherapy and lenograstim in CML patients. Twenty-three patients (62%) were successfully mobilized. Twenty-one of these patients underwent autologous stem cell transplantation later on, with a 5-year overall survival at 68%.

Fluorometric Microculture Cytotoxicity Assay was used to analyze 32 tumor cell samples from CML patients, (26 chronic phase and 6 blast crisis). Imatinib showed a higher in vitro activity and more positive drug interactions in cells from blast crisis than from chronic phase. Interferon, daunorubicin and arsenic trioxide had the greatest benefit from a combination with imatinib.

Microarray-based gene expression analyses were performed on diagnostic CML samples prior to interferon treatment. We identified six genes that were differentially expressed in responders and non-responders to interferon. It might prove possible to use gene expression analysis to predict future response to interferon.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 256
Keyword
Medicine, chronic myeloid leukemia, adult, stem cell transplantation, mobilization of Ph-negative stem cells, in vitro assay, imatinib, gene expression, Medicin
Identifiers
urn:nbn:se:uu:diva-7841 (URN)978-91-554-6878-1 (ISBN)
Public defence
2007-05-16, Enghoffsalen, Akademiska Sjukhuset, Ingång 50, bv, Uppsala, 09:15
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Available from: 2007-04-25 Created: 2007-04-25Bibliographically approved

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