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Lack of antitumor activity of recombinant endostatin in a human neuroblastoma xenograft model
E Jouanneau1, L Alberti, M Nejjari
1Département de Biologie des tumeurs, Centre León Bérard, Lyon, France.
Abstract:
Patients with metastatic neuroblastoma are rarely curable with currently available therapy, and the search for new treatment options, which include the use of inhibitors of tumor angiogenesis, is warranted. Here, we have evaluated the efficacy of one of the most promising natural inhibitors of angiogenesis described to date, endostatin, in a human neuroblastoma xenograft model in nude mice. Murine endostatin cDNA was cloned in a bacterial expression vector, expressed as a polyHis-Endostatin fusion protein and purified on Ni2+-NTA beads. The in vitro activity of soluble endostatin was confirmed on bovine capillary endothelial cells and human umbilical vein endothelial cells. The human neuroblastoma cell line SKNAS was injected subcutaneously in the flank of nude mice and administration of the recombinant angiogenesis inhibitor started when tumors reached the size of 100 microm3. Twenty mg/kg of recombinant precipitated endostatin or PBS was subcutaneously injected daily for 12 days. Serum endostatin levels were measured using a competitive enzyme immunoassay. Tumor growth was only slowed down in endostatin-treated mice when compared to control mice, and no statistically significant difference in serum levels of endostatin was observed between endostatin-treated and control groups. The lack of correlation between serum concentration and tumor response raises concern regarding the mechanism of action of endostatin.
Insights
This study investigated endostatin, a natural angiogenesis inhibitor, for treating metastatic neuroblastoma in mice. While endostatin slowed tumor growth, its effectiveness was limited, raising questions about its mechanism of action.
Area of Science:
- Oncology
- Biochemistry
- Molecular Biology
Background:
- Metastatic neuroblastoma has a poor prognosis with current therapies.
- Targeting tumor angiogenesis is a promising therapeutic strategy.
- Endostatin is a natural inhibitor of angiogenesis with potential anti-cancer effects.
Purpose of the Study:
- To evaluate the efficacy of endostatin in a human neuroblastoma xenograft model.
- To assess the anti-angiogenic potential of endostatin in vivo.
- To investigate the correlation between serum endostatin levels and tumor response.
Main Methods:
- Recombinant murine endostatin was expressed and purified.
- In vitro endothelial cell proliferation assays confirmed endostatin activity.
- Human neuroblastoma xenografts in nude mice were treated with endostatin or PBS.
- Serum endostatin levels were measured via competitive enzyme immunoassay.
Main Results:
- Endostatin treatment resulted in a modest but statistically insignificant slowing of tumor growth compared to controls.
- No significant difference in serum endostatin levels was observed between treatment and control groups.
- A lack of correlation between serum endostatin concentration and tumor response was noted.
Conclusions:
- Endostatin demonstrated limited efficacy in inhibiting neuroblastoma xenograft growth.
- The observed lack of correlation raises concerns about the mechanism of action and therapeutic potential of endostatin in this model.
- Further research is needed to understand endostatin's role in neuroblastoma treatment.
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