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The Selective Class III/V Receptor Tyrosine Kinase Inhibitor SU11657 Inhibits Tumor Growth and Angiogenesis in Experimental Neuroblastoma
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-90708OAI: oai:DiVA.org:uu-90708DiVA: diva2:163160
Available from: 2003-09-05 Created: 2003-09-05Bibliographically approved
In thesis
1. Treatment of Experimental Neuroblastoma with Angiogenic Inhibitors
Open this publication in new window or tab >>Treatment of Experimental Neuroblastoma with Angiogenic Inhibitors
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. 57 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1279
Medicine, Angiogenesis, Neuroblastoma, MYCN, VEGF, SU11657, SU5416, TNP-470, zoledronic acid, Medicin
National Category
Dermatology and Venereal Diseases
urn:nbn:se:uu:diva-3536 (URN)91-554-5703-7 (ISBN)
Public defence
2003-09-26, B21, BMC, Uppsala, 13:15
Available from: 2003-09-05 Created: 2003-09-05 Last updated: 2013-03-22Bibliographically approved

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