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Significant cytotox...
Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia.
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- Lindhagen, Elin (author)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics
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- Eriksson, Anna (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Haematology
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- Wickström, Malin (author)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics
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- Danielsson, Katarina (author)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics
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- Grundmark, Birgitta (author)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics/Rolf Larsson
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- Henriksson, Roger (author)
- Umeå universitet,Onkologi
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- Nygren, Peter (author)
- Uppsala universitet,Enheten för onkologi,Nygren
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- Åleskog, Anna (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Haematology
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- Larsson, Rolf (author)
- Uppsala universitet,Klinisk farmakologi,Cancer Pharmacology and Informatics
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- Höglund, Martin (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Haematology
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(creator_code:org_t)
- Wiley, 2008
- 2008
- English.
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In: Eur J Haematol. - : Wiley. - 1600-0609 .- 0902-4441. ; 81:5, s. 344-353
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- OBJECTIVES:Gefitinib inhibits epidermal growth factor receptor (EGFR) signalling, but may also act by non-EGFR dependent mechanisms. We have investigated the activity of gefitinib in haematological tumour cells, in particular acute myeloblastic leukaemia (AML).METHODS:Cytotoxic activity of gefitinib, alone or in combination with standard anti-leukaemic drugs, was assessed by the short-term fluorometric microculture cytotoxicity assay in tumour cells from 117 patients representing five haematological and five non-haematological malignancies. In AML, the EGFR status was analysed by immunochemistry. Gefitinib-induced apoptosis was investigated in a subset of AML samples, as well as in the leukaemia cell line MV-4-11, using a multiparametric high content screening assay. To confirm activation of caspase-3 in cells treated with gefitinib, a blocking test was carried out in which MV4-11 cells were pretreated with the specific caspase inhibitor DEVD-FMK.RESULTS:Gefitinib showed highest cytotoxic activity in AML (n = 19) with many samples being sensitive at concentrations achievable in clinical practice (<10 microM), and no difference between previously untreated and relapsed patients. No correlation between the activity of gefitinib and standard antileukaemic drugs (cytarabine, doxorubicin, etoposide) was observed. Combining gefitinib with these drugs resulted in mainly additive or synergistic (etoposide) effects, with no evidence of sequence dependency. The AML cells did not express the EGFR. Gefitinib induced apoptosis, which was at least partly mediated by activation of the caspase-3 pathway.CONCLUSION:In vitro, gefitinib has significant cytotoxic activity in AML by inducing apoptosis through non-EGFR dependent pathways.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Keyword
- acute myeloblastic leukaemia
- gefitinib
- targeted therapy
- chemotherapy
- new drug development
- individualised tumour response testing
- MEDICINE
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lindhagen, Elin
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Eriksson, Anna
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Wickström, Malin
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Danielsson, Kata ...
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Grundmark, Birgi ...
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Henriksson, Roge ...
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show more...
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Nygren, Peter
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Åleskog, Anna
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Larsson, Rolf
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Höglund, Martin
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
- Articles in the publication
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Eur J Haematol
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European Journal ...
- By the university
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Umeå University
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Uppsala University