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Experimental therapies of malignant glioma: with emphasis on angiogenesis inhibition
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant glioma consists of a group of diseases where the localisation and the nature of the disease makes treatment an extreme challenge. Two important biological features of malignant glioma cells are their infiltrative growth and their ability to induce angiogenesis. Glioma cells migrate extensively behind the blood-brain barrier and infiltrate the surrounding brain making radical treatment with surgery and radiotherapy almost impossible.

The aims of this thesis were to investigate factors of importance for glioma cell migration and angiogenesis and to evaluate if an anti-angiogenesis approach alone or in combination with current treatment modalities could inhibit glioma growth. For this purpose we used the BT4C orthotopic rat glioma model and investigated treatment effects of the vascular endothelial growth factor (VEGF) receptor-2 and epidermal growth factor (EGF) receptor tyrosine kinase inhibitor ZD6474 alone or in combination with temozolomide or radiotherapy. Altered protein expression pattern after anti-angiogenesis treatment was measured using a mass-spectrometric proteomic method, followed by multivariate data-analysis.

The tissue plasminogen activator (tPA), urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and VEGF showed altered temporal and spatial mRNA expression during glioma progression. In early stages of tumour progression the expression was found throughout the tumour while in later stages, the expression was more predominant in the invasive tumour border.

ZD6474 in monotherapy significantly inhibited tumour growth in the BT4C glioma model. The effect was further enhanced when combined with radiotherapy or temozolomide. Using mass-spectrometric methods an altered protein expression pattern after ZD6474 treatment was observed implicating the possibility to use proteomic methods for finding predictive biomarkers for anti-angiogenesis treatment.

In conclusion, this thesis demonstrates a co-expression of factors important for glioma growth and angiogenesis and that treatment with an angiogenesis inhibitor has additive effects on glioma growth when combined with radiotherapy and chemotherapy. Finally, an altered protein expression pattern after anti-angiogenesis treatment is evident and detectable. Hopefully this work will contribute to and encourage further research to reach a better understanding of how to combine and evaluate different treatment approaches in malignant glioma.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2008. , 76 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1219
Keyword [en]
glioma, angiogenesis, VEGF, tyrosinekinaseinhibitor, ZD6474, plasminogenactivator, tPA, uPA, proteomics
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-1955ISBN: 978-91-7264-667-4 (print)OAI: oai:DiVA.org:umu-1955DiVA: diva2:142556
Public defence
2009-01-23, Betula, 6M, Norrlands Universitets Sjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2012-04-03Bibliographically approved
List of papers
1. VEGF and tPA co-expressed in malignant glioma
Open this publication in new window or tab >>VEGF and tPA co-expressed in malignant glioma
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1997 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 36, no 6, 615-618 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3720 (URN)
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2017-12-14Bibliographically approved
2. Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression
Open this publication in new window or tab >>Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression
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1999 (English)In: International Journal of Developmental Neuroscience, ISSN 0736-5748, E-ISSN 1873-474X, Vol. 17, no 5, 473-481 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-3721 (URN)
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2017-12-14Bibliographically approved
3. The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model
Open this publication in new window or tab >>The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model
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2004 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 91, no 6, 1174-1180 p.Article in journal (Refereed) Published
Keyword
glioma, ZD6474, angiogenesis, VEGF, tyrosine kinase inhibitor
Identifiers
urn:nbn:se:umu:diva-15551 (URN)doi:10.1038/sj.bjc.6602108 (DOI)15305185 (PubMedID)
Available from: 2007-11-23 Created: 2007-11-23 Last updated: 2017-12-14Bibliographically approved
4. Effects of the VEGFR inhibitor ZD6474 in combination with radiotherapy and temozolomide in an orthotopic glioma model.
Open this publication in new window or tab >>Effects of the VEGFR inhibitor ZD6474 in combination with radiotherapy and temozolomide in an orthotopic glioma model.
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2008 (English)In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 88, no 1, 1-9 p.Article in journal (Refereed) Published
Abstract [en]

AIM OF THE STUDY:

The extensive neovascularisation of malignant glioma is mainly influenced by vascular endothelial growth factor (VEGF). The effect of ZD6474, a potent inhibitor of VEGF-receptor-2, was evaluated in combination with either radiotherapy or temozolomide.

METHODS:

The effects on glioma growth were investigated in the intracerebral BT4C rat glioma model. ZD6474 30 mg/kg was given alone or in combination with radiotherapy 12 Gy x 1 or with temozolomide 100 mg/kg for 3 days. Two different experiments were performed comparing ZD6474 to radiotherapy or temozolomide. For each experiment 28 animals were randomized into four groups.

RESULTS:

ZD6474 in combination with radiotherapy significantly decreased tumour area by 66% compared with controls whereas the combination with temozolomide decreased tumour area by 74%.

CONCLUSIONS:

ZD6474 in combination with two standard modalities in the treatment of malignant glioma, radiotherapy and chemotherapy, markedly decreased the growth of an intracerebral experimental glioma. These results justify further investigations of these therapies in combination.

Keyword
Angiogenesis, Glioma, Radiotherapy, Temozolomide, VEGF, ZD6474
Identifiers
urn:nbn:se:umu:diva-9545 (URN)doi:10.1007/s11060-008-9527-3 (DOI)18228115 (PubMedID)
Available from: 2008-04-22 Created: 2008-04-22 Last updated: 2017-12-14Bibliographically approved
5. Treatment with the angiogenesis inhibitor vandetanib (ZD6474) alters proteomic pattern
Open this publication in new window or tab >>Treatment with the angiogenesis inhibitor vandetanib (ZD6474) alters proteomic pattern
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3724 (URN)
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2010-01-13Bibliographically approved

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