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The Anti-VEGF Antibody Bevacizumab Potently Reduces the Growth Rate of High-Risk Neuroblastoma Xenografts
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2006 (English)In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 60, no 5, 576-581 p.Article in journal (Refereed) Published
Abstract [en]

Neuroblastoma (NB) is a rapidly growing, well-vascularized childhood cancer that often presents with metastases. The overall five-year survival in NB is approximately 45% despite multimodality treatment, and therefore there is a clinical need for new therapeutic strategies. NB frequently overexpresses the angiogenic factor VEGF (vascular endothelial growth factor). The aim of this study was to investigate the effect of bevacizumab (Avastin, Genentech/Roche), a humanized anti-VEGF-A antibody, on NB growth in three different xenograft models, chosen to resemble high-risk NB. The human NB cell lines SK-N-AS, IMR-32 and SH-SY5Y, which are poorly differentiated and overexpress VEGF-A, were injected s.c. in immunodeficient mice. Bevacizumab was given intraperitoneally twice weekly at 5 mg/kg body weight, starting at a tumor volume of 0.3 mL. Bevacizumab significantly (p < 0.01-0.05) reduced NB growth in vivo without toxicity by causing a 30-63% reduction of angiogenesis, but had no effect on NB cell survival in vitro. Serum concentrations of VEGF-A increased two- to six-fold during bevacizumab therapy which did not result in faster tumor growth compared with control animals. Based on our experimental data we suggest consideration of bevacizumab in treatment of high-risk NB that does not respond to conventional therapy and that overexpresses VEGF.

Place, publisher, year, edition, pages
2006. Vol. 60, no 5, 576-581 p.
Keyword [en]
angiogenesis, bevacizumab, neuroblastoma, VEGF-A, human
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-98023DOI: 10.1203/01.pdr.0000242494.94000.52ISI: 000241570300013PubMedID: 16988184OAI: oai:DiVA.org:uu-98023DiVA: diva2:173182
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Novel Treatment Modalities for High-Risk Neuroblastoma: Studies in Animal Models
Open this publication in new window or tab >>Novel Treatment Modalities for High-Risk Neuroblastoma: Studies in Animal Models
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuroblastoma, the most common extracranial solid tumor of childhood, is a heterogeneous tumor. In some patients, the tumor can go into spontaneous regression and disappear whereas other patients have rapidly growing tumors with a poor prognosis. The overall long-term survival rate in patients with high-risk neuroblastoma is less than 30%, indicating the need for new treatment strategies.

Angiogenesis inhibition hampers the formation of new blood vessels, thereby limiting the tumors’ metabolic exchange. Neuroblastoma is rapidly growing and high tumor angiogenesis has been associated with poor outcome. Therefore, the aim of this thesis was to investigate the effect of novel treatment modalities for angiogenesis inhibition on high-risk neuroblastoma xenografts. For that purpose, we used subcutaneous mouse models and characterized orthotopic mouse models for high-risk neuroblastoma.

We found that xenotransplantation of neuroblastoma cells into the adrenal gland of SCID and SCID beige mice resulted in orthotopic tumors resembling clinical neuroblastoma in respect to tumor site, growth and spread. Using contrast-enhanced ultrasound, we observed that the receptor tyrosine kinase inhibitor SU11248 reduced orthotopic neuroblastoma growth and spread by reducing tumor angiogenesis.

In subcutaneous xenografts for high-risk neuroblastoma, valuable for studies requiring continuous assessment of tumor volume, we demonstrated that immune-neutralizing VEGF with the anti-VEGF antibody bevacizumab significantly reduced neuroblastoma growth.

Finally, we found that formulations of the chemotherapeutic drug GMX1778 inhibited angiogenesis and induced tumor regression in a dose dependent manner without host toxicity. We showed that relapsing tumors remained responsive to GMX-therapy without accelerated growth or induced drug resistance.

In conclusion, SU11248, bevacizumab, and formulations of the active compound GMX1778 may become useful for treating high-risk neuroblastoma.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2009. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 416
Keyword
neuroblastoma, bevacizumab, SU11248, GMX1778, GMX1777, animal model
National Category
Clinical Science
Identifiers
urn:nbn:se:uu:diva-9544 (URN)978-91-554-7399-0 (ISBN)
Public defence
2009-02-27, C4:305, BMC, Husargatan 3, Uppsala, 09:15
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Supervisors
Available from: 2009-02-06 Created: 2009-02-06Bibliographically approved

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Fuchs, DieterChristofferson, RolfAzarbayjani, Faranak

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