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Experimental studies in brain tumours: with special regard to multidrug resistance and the ErbB-family
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary brain tumours, and especially the most common form malignant gliomas, usually display a pronounced resistance to other treatment modalities when surgery fails to cure. Growth factors, such as EGF and its receptor, frequently amplified and overexpressed in malignant gliomas, and factors associated with multidrug resistance have been suggested to at least partially explain the poor outcome. The aim of this thesis was to characterise factors in primary brain tumours associated with the development of resistance with focus on the epidermal growth factor receptor (ErbB) family, and multidrug resistance (MDR).

Influences of irradiation on the expression and activity of P-glycoprotein (Pgp) in malignant gliomas was evaluated. The effects showed that irradiation increased the efflux activity of Pgp in rat brain vascular endothelial cells, but not in glioma cells. In the intracranial BT4C glioma model, Pgp was detected in the capillary endothelium in the tumour tissue but not in glioma cells.

Expression of several factors coupled to MDR (Pgp, MRP1, LRP, and MGMT) in primary brain tumours were analysed and correlated to clinical data. In gliomas, Pgp and MRP1 were predominantly observed in capillary endothelium and in scattered tumour cells, whereas LRP occurred only in tumour cells. In meningiomas, expression of the analysed markers was demonstrated in the capillary endothelium, with a higher expression of Pgp and MRP1 in transitional compared to meningothelial meningiomas. A pronounced expression of MGMT was found independently of the histopathological grade or tumour type. Survival analysis indicated a shorter overall survival for patients suffering from low-grade gliomas with high expression of Pgp.

To explore the importance of the epidermal growth factor receptor (EGFR), expression levels of the family members (EGFR, ErbB2-4) were analysed and their relations to various clinical parameters were evaluated in gliomas and meningiomas. In gliomas, the highest EGFR expression was observed in high-grade tumours, while ErbB4 expression was most pronounced in low-grade tumours. In meningiomas, expression of EGFR, ErbB2, and ErbB4 was observed in the majority of the tumours. An intriguing observation in low-grade gliomas was a significantly decreased overall survival for patients with high EGFR protein expression.

The effects of different time schedules for administration of the selective EGFR inhibitor ZD1839 in relation to irradiation of glioma cells were analysed. The analyses showed a heterogeneity in the cytotoxic effects of ZD1839 between cell lines, and it was obvious that some of the cell lines showed sensitivity to ZD1839 despite no or low expression of EGFR. The study also demonstrated the importance of timing of ZD1839 administration when this agent is combined with irradiation.

In conclusion, in order to enhance the efficacy of radiotherapy by various drugs in malignant gliomas it may be essential to inhibit drug efflux activity in endothelial cells and to deliver drugs in an optimal timing in relation to radiotherapy. The heterogeneity in expression of drug resistance markers, as well as the ErbB family reflects the complexity in classification of primary brain tumours, and indicates that subgroups of patients with low-grade gliomas expressing Pgp and EGFR might benefit from more aggressive and individualised treatment.

Place, publisher, year, edition, pages
Umeå: Strålningsvetenskaper , 2005. , 80 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 959
Keyword [en]
Oncology, glioma, meningioma, endothelium, MDR, Pgp, MRP1, LRP, MGMT, EGFR, ErbB2, ErbB3, ErbB4
Keyword [sv]
Onkologi
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-521ISBN: 91-7305-863-7 (print)OAI: oai:DiVA.org:umu-521DiVA: diva2:143693
Public defence
2005-05-20, Sal 244, Lionssalen, By 7, Norrlands Universitetssjukhus, UMEÅ, 12:00 (English)
Opponent
Supervisors
Available from: 2005-04-28 Created: 2005-04-28 Last updated: 2012-04-03Bibliographically approved
List of papers
1. Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation
Open this publication in new window or tab >>Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation
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2002 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, no 1, 1-9 p.Article in journal (Refereed) Published
Abstract [en]

The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

Keyword
Glioma, P-glycoprotein, drug resistance, blood-brain barrier, irradiation
Identifiers
urn:nbn:se:umu:diva-4545 (URN)10.1385/MO:19:1:1 (DOI)
Available from: 2005-04-28 Created: 2005-04-28 Last updated: 2017-12-14Bibliographically approved
2. Heterogeneity in the expression of markers for drug resistance in brain tumors
Open this publication in new window or tab >>Heterogeneity in the expression of markers for drug resistance in brain tumors
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2004 (English)In: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, no 1, 21-27 p.Article in journal (Refereed) Published
Abstract [en]

Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.

Keyword
Pgp, MRP1, LRP, MGMT, glioma, meningioma
Identifiers
urn:nbn:se:umu:diva-14978 (URN)14986930 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
3. Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas
Open this publication in new window or tab >>Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas
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2004 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, no 2, 135-142 p.Article in journal (Refereed) Published
Abstract [en]

Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

Keyword
Epidermal growth factor receptor, ErbB2, ErbB3, ErbB4, gliomas, meningiomas
Identifiers
urn:nbn:se:umu:diva-14988 (URN)doi:10.1007/s00401-004-0875-6 (DOI)15148612 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
4. Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro.
Open this publication in new window or tab >>Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro.
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2007 (English)In: Acta Oncologica, ISSN 0284-186X, Vol. 46, no 7, 951-960 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-16740 (URN)doi:10.1080/02841860701253045 (DOI)
Available from: 2007-10-10 Created: 2007-10-10 Last updated: 2012-04-03Bibliographically approved

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