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Application of a New Logic to Old Drugs: Angiogenesis Inhibition in Neuroblastoma
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuroblastoma is one of the most common solid cancers of early childhood. In Sweden, approximately 10-15 cases occur annually. The overall five-year neuroblastoma survival in Europe is approximately 45%. Since cancer treatment involves drugs with risks of side effects in the growing child, there is a need for more effective and less toxic drugs. One new approach in cancer treatment is inhibition of tumor angiogenesis, i.e., of new blood vessel growth into the tumor. An angiogenesis inhibitor may be combined with cytostatic drugs to enhance the efficacy. The aim of this study was to investigate how drugs could be used to inhibit angiogenesis and tumor growth in a xenograft model of human neuroblastoma in nude mice.

The tumors express the angiogenesis stimulator vascular endothelial growth factor (VEGF) on both protein and mRNA levels. The angiogenesis inhibitors SU5416 (an inhibitor of VEGF signalling) and TNP-470 (an inhibitor of endothelial cell proliferation) inhibited angiogenesis in our model. TNP-470, however, inhibited angiogenesis without significant reduction of the tumor growth, in contrast to SU5416.

We also discovered that the cytostatic drug CHS 828 could cause regression of neuroblastoma tumors in the model when given orally at a low daily dose, alone or in combination with the angiogenesis inhibitor SU5416 or TNP-470.

Furthermore, a new use of the cardiac glycoside digoxin was found. Digoxin inhibited FGF-2 -stimulated bovine capillary endothelial cell growth in vitro, and inhibited angiogenesis in vivo in the chick chorioallantoic membrane assay (CAM). It also inhibited neuroblastoma growth by approximately 50% in our neuroblastoma model.

In conclusion, CHS 828 and digoxin represent two classes of drugs with potent antitumor effects that may be valuable in treatment of neuroblastoma, either alone or in combination with angiogenesis inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 39
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1254
Keywords [en]
Cell biology, angiogenesis, neuroblastoma, CHS 828, digoxin, combination treatment
Keywords [sv]
Cellbiologi
National Category
Cell Biology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-3458ISBN: 91-554-5612-X (print)OAI: oai:DiVA.org:uu-3458DiVA, id: diva2:162894
Public defence
2003-06-04, B21, Biomedical Centre (BMC), Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-05-14 Created: 2003-05-14Bibliographically approved
List of papers
1. Angiogenesis can be reduced without significant reduction of tumor growth
Open this publication in new window or tab >>Angiogenesis can be reduced without significant reduction of tumor growth
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2007 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 27, no 6B, p. 3883-3889Article in journal (Refereed) Published
Abstract [en]

Background: High risk neuroblastoma (NB) patients have an overall five-year survival of similar to 50%, indicating the need for new treatment strategies, such as angiogenesis inhibition. Materials and Methods: The angiogenesis inhibitor TNP-470 (30 mg/kg, every other day, subcutaneously) was given to nude mice with subcutaneous human neuroblastoma xenografts. The plasma concentrations of the angiogenesis stimulators, i.e. vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and hepatocyte growth factor (HGF), were assayed longitudinally. Angiogenesis, proliferation and apoptosis were quantified on tumor tissue slides. Results: Upon treatment with TNP-470, angiogenesis was significantly inhibited by the reduction of length and surface area of vessels per tumor volume, without having significant effect on tumor growth, tumor cell proliferation or apoptosis. Plasma concentrations of VEGF-A per tumor volume were significantly increased upon treatment. Conclusion: Angiogenesis inhibition must reach a threshold before significant tumor cell apoptosis and a reduction of the tumor growth rate occur.

Keywords
TNP-470, angiogenesis inhibition, angiogenesis threshold, angiogenesis stimulators, neuroblastoma, mice
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90511 (URN)000251901700015 ()18225546 (PubMedID)
Available from: 2003-05-14 Created: 2003-05-14 Last updated: 2017-12-14Bibliographically approved
2. Importance of Vascular Endothelial Growth Factor A in the Progression of Experimental Neuroblastoma
Open this publication in new window or tab >>Importance of Vascular Endothelial Growth Factor A in the Progression of Experimental Neuroblastoma
2002 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 5, no 4, p. 267-274Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.

Keywords
Angiogenesis Inhibitors/pharmacology, Animals, Cell Division/drug effects, Endothelial Growth Factors/blood/*physiology, Female, Humans, Indoles/pharmacology, Male, Mice, Mice; Nude, Neoplasms; Experimental/drug therapy/etiology/metabolism, Neuroblastoma/drug therapy/*etiology/metabolism, Protein-Tyrosine Kinase/antagonists & inhibitors, Pyrroles/pharmacology, Research Support; Non-U.S. Gov't, Transplantation; Heterologous, Tumor Cells; Cultured, Vascular Endothelial Growth Factor A
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90512 (URN)10.1023/A:1024564817563 (DOI)12906318 (PubMedID)
Available from: 2003-05-14 Created: 2003-05-14 Last updated: 2017-12-14Bibliographically approved
3. CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs
Open this publication in new window or tab >>CHS 828 inhibits neuroblastoma growth in mice alone and in combination with antiangiogenic drugs
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2002 In: Pediatric Research, ISSN 0031-3998, Vol. 51, no 5, p. 607-611Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90513 (URN)
Available from: 2003-05-14 Created: 2003-05-14Bibliographically approved
4. Digoxin inhibits angiogenesis and tumor growth in mice
Open this publication in new window or tab >>Digoxin inhibits angiogenesis and tumor growth in mice
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90514 (URN)
Available from: 2003-05-14 Created: 2003-05-14Bibliographically approved

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