Inhibition of tumor angiogenesis by oral etoposide

Panigrahy,Dipak; Kaipainen,Arja; Butterfield,Catherine  E.; Chaponis,Deviney   M.; Laforme,Andrea   M.; Folkman,Judah; Kieran,Mark   W.

doi:10.3892/etm.2010.127

Inhibition of tumor angiogenesis by oral etoposide

Authors:
- Dipak Panigrahy
- Arja Kaipainen
- Catherine E. Butterfield
- Deviney M. Chaponis
- Andrea M. Laforme
- Judah Folkman
- Mark W. Kieran
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Affiliations: Vascular Biology Program, Children's Hospital Boston, Department of Surgery, Harvard Medical School, Boston, MA, USA, Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada, Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
Published online on: July 21, 2010 https://doi.org/10.3892/etm.2010.127
Pages: 739-746

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Abstract

The chemotherapeutic agent etoposide is a topoisomerase II inhibitor widely used for cancer therapy. Low-dose oral etoposide, administered at close regular intervals, has potent anti-tumor activity in patients who are refractory to intravenous etoposide; however, the mechanism remains unclear. Since endothelial cells may be more sensitive than tumor cells to chemotherapy agents, we determined the effects of etoposide alone and in combination with oral cyclooxygenase-2 inhibitors and peroxisome-proliferator activated receptor γ ligands on angiogenesis and tumor growth in xenograft tumor models. Optimal anti-angiogenic (metronomic) and anti-tumor doses of etoposide on angiogenesis, primary tumor growth and metastasis were established alone and in combination therapy. Etoposide inhibited endothelial and tumor cell proliferation, decreased vascular endothelial growth factor (VEGF) production by tumor cells and suppressed endothelial tube formation at non-cytotoxic concentrations. In our in vivo studies, oral etoposide inhibited fibroblast growth factor 2 and VEGF-induced corneal neovascularization, VEGF-induced vascular permeability and increased levels of the endogenous angiogenesis inhibitor endostatin in mice. In addition, etoposide inhibited Lewis lung carcinoma (LLC) and human glioblastoma (U87) primary tumor growth as well as spontaneous lung metastasis in a LLC resection model. Furthermore, etoposide had synergistic anti-tumor activity in combination with celecoxib and rosiglitazone, which are also oral anti-angiogenic and anti-tumor agents. Etoposide inhibits angiogenesis in vitro and in vivo by indirect and direct mechanisms of action. Combining etoposide with celecoxib and rosiglitazone increases its efficacy and merits further investigation in future clinical trials to determine the potential usefulness of etoposide in combinatory anti-angiogenic chemotherapy.

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