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Heterogeneity in the expression of markers for drug resistance in brain tumors
Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurokirurgi.
Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
Visa övriga samt affilieringar
2004 (Engelska)Ingår i: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, nr 1, s. 21-27Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2004. Vol. 23, nr 1, s. 21-27
Nyckelord [en]
Pgp, MRP1, LRP, MGMT, glioma, meningioma
Identifikatorer
URN: urn:nbn:se:umu:diva-14978PubMedID: 14986930OAI: oai:DiVA.org:umu-14978DiVA, id: diva2:154650
Tillgänglig från: 2007-11-23 Skapad: 2007-11-23 Senast uppdaterad: 2018-06-09Bibliografiskt granskad
Ingår i avhandling
1. Experimental studies in brain tumours: with special regard to multidrug resistance and the ErbB-family
Öppna denna publikation i ny flik eller fönster >>Experimental studies in brain tumours: with special regard to multidrug resistance and the ErbB-family
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Strålningsvetenskaper, 2005. s. 80
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 959
Nyckelord
Oncology, glioma, meningioma, endothelium, MDR, Pgp, MRP1, LRP, MGMT, EGFR, ErbB2, ErbB3, ErbB4, Onkologi
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
onkologi
Identifikatorer
urn:nbn:se:umu:diva-521 (URN)91-7305-863-7 (ISBN)
Disputation
2005-05-20, Sal 244, Lionssalen, By 7, Norrlands Universitetssjukhus, UMEÅ, 12:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2005-04-28 Skapad: 2005-04-28 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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Andersson, UlrikaMalmer, BeatriceBrännström, ThomasHenriksson, Roger

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