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Biological markers in breast cancer and acute leukaemia with focus on drug resistance
Örebro University, School of Health and Medical Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2010. , p. 68
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 43
Keyword [en]
Breast cancer, acute leukaemia, drug resistance, toposiomerase IIa, BCRP, HER2, SLC25A43, flow cytometry, real time PCR, whole genome screening
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-10519ISBN: 978-91-7668-724-6 (print)OAI: oai:DiVA.org:oru-10519DiVA, id: diva2:314058
Public defence
2010-05-21, Bohmanssonsalen, Universitetssjukhuset, Örebro, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-10-18Bibliographically approved
List of papers
1. Topoisomerase II-α expression in different cell cycle phases in fresh human breast carcinomas
Open this publication in new window or tab >>Topoisomerase II-α expression in different cell cycle phases in fresh human breast carcinomas
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2002 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 15, no 5, p. 486-491Article in journal (Refereed) Published
Abstract [en]

Topoisomerase II-alfa (topo IIalfa) is the key target enzyme for the topoisomerase inhibitor class of anti-cancer drugs. In normal cells, topo IIalfa is expressed predominantly in the S/G2/M phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo IIalfa is both higher and less dependent on proliferation state in the cell. We studied fresh specimens from 50 cases of primary breast cancer. The expression of topo IIalfa in different cell cycle phases was analyzed with two-parameter flow cytometry using the monoclonal antibody SWT3D1 and propidium iodide staining. The expression of topo IIalfa was significantly higher in the S/G2/M phase of the cell cycle than in the G0/G1 phase in both DNA diploid and DNA nondiploid tumors. In 18 of 21 diploid tumors, and in 25 of 29 nondiploid tumors, >50% of the topo IIalfa–positive cells were in the G0/G1 phase. This significant expression of topo IIalfa in the G0/G1 phase of the cell cycle may have clinically important implications for treatment efficacy of topoisomerase II inhibitors.

Place, publisher, year, edition, pages
Baltimore: Lippincott Williams & Wilkins, 2002
Keyword
breast cancer, cell cycle, DNA flow cytometry, topoisomerase IIa
National Category
Medical and Health Sciences
Research subject
Medicine; Biomedicine
Identifiers
urn:nbn:se:oru:diva-10515 (URN)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-12-12Bibliographically approved
2. Topoisomerase IIα mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia
Open this publication in new window or tab >>Topoisomerase IIα mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia
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2007 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 31, no 1, p. 153-160Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.

Place, publisher, year, edition, pages
Athens: Editorial Academy of the International Journal of Oncology, 2007
Keyword
topoisomerase IIa, acute leukaemia, drug resistance, prognosis, reverse transcriptase-polymerase chain reaction, flow cytometry
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine; Biomedicine
Identifiers
urn:nbn:se:oru:diva-10516 (URN)17549416 (PubMedID)2-s2.0-34548571944 (Scopus ID)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-12-12Bibliographically approved
3. Topoisomerase IIalpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C
Open this publication in new window or tab >>Topoisomerase IIalpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C
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2009 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 6, p. 1527-1531Article in journal (Refereed) Published
Abstract [en]

Patients diagnosed with acute myeloid leukaemia are often treated with a combination of daunorubicin and 1-β-D-arabinofuranosylcytosine (ara-C). Both daunorubicin and ara-C exert their effects in the cell nucleus but by different mechanisms, i.e. daunorubicin causes double stranded DNA breaks by inhibition of the nuclear enzyme, topoisomerase (topo) IIα, whereas ara-C is an anti-metabolite that integrates with DNA during DNA synthesis and causes cell cycle arrest. Despite the initial efficacy of these drugs, resistance often develops in the clinical setting. The mechanisms underlying clinical resistance to these drugs are poorly understood, but may be associated with an increase in the proportion of topo IIα negative cells. Therefore, the aim of this study was to determine whether daunorubicin treatment results in increased numbers of topo IIα negative subpopulations in vitro. Acute myeloid leukaemia cells isolated from 12 consenting patients were treated for 24 h with increasing concentrations of daunorubicin or ara-C and the proportion of topo IIα-negative cells in surviving cell populations determined by flow cytometry. Treatment with daunorubicin, but not ara-C, resulted in a significant increase in the proportion of topo IIα negative cells (p=0.0023). These results suggest that daunorubicin may act by cell cycle arrest and/or by selection of pre-existing topo IIα negative subpopulations. Both of these mechanisms can theoretically contribute to a reduced efficacy of a second dose of daunorubicin. The clinical relevance of these interactions should be further elucidated in experimental and clinical studies.

Place, publisher, year, edition, pages
Athen: Spandidos Publications, 2009
Keyword
acute myeloid leukaemia, topoisomerase, daunorubicin, 1-b-D-arabinofuranosylcytosine, flow cytometry
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Medicine; Biomedicine
Identifiers
urn:nbn:se:oru:diva-10517 (URN)10.3892/or_00000597 (DOI)000271732300035 ()19885609 (PubMedID)2-s2.0-70449353711 (Scopus ID)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-12-12Bibliographically approved
4. BCRP mRNA expression v. clinical outcome in 40 adult AML patients
Open this publication in new window or tab >>BCRP mRNA expression v. clinical outcome in 40 adult AML patients
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2005 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, no 2, p. 141-146Article in journal (Refereed) Published
Abstract [en]

Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain. In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2005
Keyword
Breast cancer resistance protein, acute myeloid leukaemia, drug resistance, prognosis, reverse transcriptase polymerase chain reaction
National Category
Medical and Health Sciences
Research subject
Medicine; Biomedicine
Identifiers
urn:nbn:se:oru:diva-10518 (URN)10.1016/j.leukres.2004.06.004 (DOI)000226269500006 ()15607361 (PubMedID)2-s2.0-10644230985 (Scopus ID)
Available from: 2010-04-27 Created: 2010-04-27 Last updated: 2017-12-12Bibliographically approved
5. A novel finding: SLC25A43 a solute carrier protein that is implicated in HER2 positive breast cancer
Open this publication in new window or tab >>A novel finding: SLC25A43 a solute carrier protein that is implicated in HER2 positive breast cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-10471 (URN)
Available from: 2010-04-26 Created: 2010-04-23 Last updated: 2017-10-18Bibliographically approved

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