Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Novel Treatment Modalities for High-Risk Neuroblastoma: Studies in Animal Models
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
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 [en]
neuroblastoma, bevacizumab, SU11248, GMX1778, GMX1777, animal model
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:uu:diva-9544ISBN: 978-91-554-7399-0 (print)OAI: oai:DiVA.org:uu-9544DiVA: diva2:173186
Public defence
2009-02-27, C4:305, BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2009-02-06 Created: 2009-02-06Bibliographically approved
List of papers
1. The Anti-VEGF Antibody Bevacizumab Potently Reduces the Growth Rate of High-Risk Neuroblastoma Xenografts
Open this publication in new window or tab >>The Anti-VEGF Antibody Bevacizumab Potently Reduces the Growth Rate of High-Risk Neuroblastoma Xenografts
Show others...
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.

Keyword
angiogenesis, bevacizumab, neuroblastoma, VEGF-A, human
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98023 (URN)10.1203/01.pdr.0000242494.94000.52 (DOI)000241570300013 ()16988184 (PubMedID)
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2011-05-17Bibliographically approved
2. Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments
Open this publication in new window or tab >>Regression of orthotopic neuroblastoma in mice by targeting the endothelial and tumor cell compartments
Show others...
2009 (English)In: Journal of Translational Medicine, ISSN 1479-5876, Vol. 7, 16- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: High-risk neuroblastoma has an overall five-year survival of less than 40%, indicating a need for new treatment strategies such as angiogenesis inhibition. Recent studies have shown that chemotherapeutic drugs can inhibit angiogenesis if administered in a continuous schedule. The aim of this study was primarily to characterize tumor spread in an orthotopic, metastatic model for aggressive, MYCN-amplified neuroblastoma and secondarily to study the effects of daily administration of the chemotherapeutic agent CHS 828 on tumor angiogenesis, tumor growth, and spread. METHODS: MYCN-amplified human neuroblastoma cells (IMR-32, 2 x 10(6)) were injected into the left adrenal gland in SCID mice through a flank incision. Nine weeks later, a new laparotomy was performed to confirm tumor establishment and to estimate tumor volume. Animals were randomized to either treatment with CHS 828 (20 mg/kg/day; p.o.) or vehicle control. Differences between groups in tumor volume were analyzed by Mann-Whitney U test and in metastatic spread using Fisher's exact test. Differences with p < 0.05 were considered statistically significant. RESULTS: The orthotopic model resembled clinical neuroblastoma in respect to tumor site, growth and spread. Treatment with CHS 828 resulted in tumor regression (p < 0.001) and reduction in viable tumor fraction (p < 0.001) and metastatic spread (p < 0.05) in correlation with reduced plasma levels of the putative tumor marker chromogranin A (p < 0.001). These effects were due to increased tumor cell death and reduced angiogenesis. No treatment-related toxicities were observed. CONCLUSION: The metastatic animal model in this study resembled clinical neuroblastoma and is therefore clinically relevant for examining new treatment strategies for this malignancy. Our results indicate that daily scheduling of CHS 828 may be beneficial in treating patients with high-risk neuroblastoma.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98024 (URN)10.1186/1479-5876-7-16 (DOI)000265143500001 ()19284605 (PubMedID)
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2017-01-25Bibliographically approved
3. SU11248-mediated angiogenesis inhibition reduces tumor growth and spread in orthotopic neuroblastoma in mice monitored with contrast-enhanced ultrasound
Open this publication in new window or tab >>SU11248-mediated angiogenesis inhibition reduces tumor growth and spread in orthotopic neuroblastoma in mice monitored with contrast-enhanced ultrasound
(English)Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-98025 (URN)
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2011-01-11Bibliographically approved
4. Metronomic GMX1777 results in tumor regression and vessel maturation in subcutaneous neuroblastoma in mice without inducing drug resistance
Open this publication in new window or tab >>Metronomic GMX1777 results in tumor regression and vessel maturation in subcutaneous neuroblastoma in mice without inducing drug resistance
Show others...
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-98026 (URN)
Available from: 2009-02-06 Created: 2009-02-06 Last updated: 2011-06-28Bibliographically approved

Open Access in DiVA

fulltext(2092 kB)793 downloads
File information
File name FULLTEXT01.pdfFile size 2092 kBChecksum MD5
812f5548b40b8542e88dd22ad93372ea8d106f8ff9f39fd917c52e4d56ae996e937d88ab
Type fulltextMimetype application/pdf
cover(383 kB)47 downloads
File information
File name COVER01.pdfFile size 383 kBChecksum MD5
51561782c75fee0f7b036e614a30e48ddfac2d3822c6e17cead0d6b9d4d4c09f1d66538b
Type coverMimetype application/pdf
Buy this publication >>

By organisation
Department of Medical Cell Biology
Clinical Science

Search outside of DiVA

GoogleGoogle Scholar
Total: 793 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 1071 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf