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Treatment of Experimental Neuroblastoma with Angiogenic Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuroblastoma is a childhood cancer that originates from neuroblasts in the peripheral nervous system. Neuroblastoma show considerable heterogeneity with respect to location, responsiveness to treatment and prognosis. Since current therapy involves drugs with risk of serious side effects in the growing child, there is a clinical need for more effective and less toxic treatment strategies.

Angiogenesis, the formation of new blood vessels, is critical for tumor progression. Specific inhibition of tumor-induced angiogenesis should restrict growth of most solid tumors and thereby provide a new treatment strategy. The aim of this study was to investigate the effects of angiogenic inhibition in experimental neuroblastoma in mice.

We found that experimental neuroblastomas expressed the perhaps most potent angiogenic growth factor, VEGF-A, and that plasma VEGF-A levels correlated with tumor size. SU5416, a novel antagonist of VEGFR-1 and 2, reduced angiogenesis and tumor growth in our model. We also investigated the properties of SU11657, a new, orally available, synthetic small molecule multi-targeted tyrosine kinase inhibitor. SU11657, at a well-tolerated dose, was more potent than SU5416 in reducing tumor growth rate and angiogenesis, even in MYCN-amplified tumors. Chemotherapeutics can also inhibit angiogenesis, when administrated daily in a non-toxic dose. CHS 828, a new chemotherapeutic, given orally, alone induced complete neuroblastoma regression in 44 % of the animals. Furthermore, the bisphosphonate zoledronic acid, developed to reduce bone resorption, showed anti-tumor activity in our model. Zoledronic acid was more potent than the angiogenic inhibitor TNP-470. Thus bisphosphonates may have other beneficial properties in patients with cancer apart from preventing bone resorption.

In conclusion, SU5416, SU11657, CHS 828, and zoledronic acid represent new drugs with potent anti-tumor effects. Angiogenic inhibition as single therapy or in combination with chemotherapeutics may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood such as neuroblastoma.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 57
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1279
Keywords [en]
Medicine, Angiogenesis, Neuroblastoma, MYCN, VEGF, SU11657, SU5416, TNP-470, zoledronic acid
Keywords [sv]
Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
URN: urn:nbn:se:uu:diva-3536ISBN: 91-554-5703-7 (print)OAI: oai:DiVA.org:uu-3536DiVA, id: diva2:163163
Public defence
2003-09-26, B21, BMC, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-09-05 Created: 2003-09-05 Last updated: 2013-03-22Bibliographically approved
List of papers
1. 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
2. The Selective Class III/V Receptor Tyrosine Kinase Inhibitor SU11657 Inhibits Tumor Growth and Angiogenesis in Experimental Neuroblastoma
Open this publication in new window or tab >>The Selective Class III/V Receptor Tyrosine Kinase Inhibitor SU11657 Inhibits Tumor Growth and Angiogenesis in Experimental Neuroblastoma
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90708 (URN)
Available from: 2003-09-05 Created: 2003-09-05Bibliographically 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
Show others...
2002 In: Pediatric Research, Vol. 51, no 5, p. 607-611Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90709 (URN)
Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved
4. The Bisphosphonate Zoledronic Acid Reduces Experimental Neuroblastoma Growth by Interference with Tumor Angiogenesis
Open this publication in new window or tab >>The Bisphosphonate Zoledronic Acid Reduces Experimental Neuroblastoma Growth by Interference with Tumor Angiogenesis
2008 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, no 3A, p. 1551-1557Article in journal (Refereed) Published
Abstract [en]

Background: Zoledronic acid is a new member of the bisphosphonate (BP) class of compounds, a family of closely related synthetic molecules originally derived from the naturally occurring pyrophosphate. These compounds that are potent inhibitors of bone resorption, have been shown to reduce the growth of several cancer cell lines in vitro, and can act as inhibitors of angiogenesis. The angiogenesis inhibitor TNP-470, a synthetic analogue of the fungal antibiotic fumagillin, has been shown to inhibit the growth of multiple tumors in vivo, and is currently in Phase H clinical trials for cancer. Materials and Methods: The effects of daily subcutaneous (s.c.) administration of zoledronic acid (0.1 mg/kg) were compared with those of TNP-470 (15 mg/kg/day and 30 mg/kg every other day, s.c.) in a nude mouse xenograft model for the childhood cancer, neuroblastoma (NB). Results: Zoledronic acid reduced the tumor growth by 33% whereas TNP-470 was less effective and reduced the tumor growth by 26% and 11% for animals treated with 15 mg/kg/day and 30 mg/kg every other day, respectively. Analysis of angiogenesis showed a significant reduction of the number of vessels per grid and in vessel length in all the treatment groups. Conclusion: Zoledronic acid shows tumoristatic and angiostatic properties that might be beneficial in the treatment of solid tumors such as neuroblastoma.

Keywords
angiogenesis, zoledronic acid, TNP-470, neuroblastoma, SH-SY5Y
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-90710 (URN)000256940300014 ()18630510 (PubMedID)
Available from: 2003-09-05 Created: 2003-09-05 Last updated: 2017-12-14Bibliographically approved

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