Abstract
Purpose: Different antiangiogenic approaches have been proposed in cancer treatment where therapeutic efficacy has been shown with the addition of cytotoxic agents. Here, we used SU6668, a small-molecule receptor tyrosine kinase inhibitor, to investigate the combinatorial effect with paclitaxel on the cellular populations of the developing vasculature.
Experimental Design: The effect of this combination was evaluated in vitro in a 72-hour proliferation assay on human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells derived from lungs, endothelial cells, aortic smooth muscle cells, and human ovarian carcinoma cells sensitive (1A9) and resistant (1A9-PTX22) to paclitaxel. Combination data were assessed by isobologram analysis. Cell survival was determined by terminal deoxyribonucleotide transferase–mediated nick-end labeling and Annexin V staining. The activity of the combination in vivo was evaluated in fibroblast growth factor-2–induced angiogenesis in Matrigel plugs s.c. implanted in mice. The 1A9-PTX22, paclitaxel-resistant xenograft model was used to evaluate tumor response.
Results: Combination index values and isobologram analysis showed synergy in inhibition of proliferation of HUVEC, human microvascular endothelial cells derived from lungs, and aortic smooth muscle cells. The combination induced greater apoptosis in HUVEC than the single agents. The addition of paclitaxel to the treatment with SU6668 significantly decreased the hemoglobin content and the number of CD31-positive vessels in Matrigel plugs in vivo. The combination of the drugs was more active than either single agent against 1A9-PTX22 xenografts; the tumor growth delay was accompanied by a significant reduction of vascular density.
Conclusions: These findings show that the activity of angiogenesis inhibitors on vascular cells could be potentiated when administered in combination with chemotherapeutic agents that themselves have vascular targeting properties.
- combination therapy
- angiogenesis
- RTK inhibitors
- endothelial cells
- paclitaxel
Footnotes
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Grant support: Associazione Italiana per la Ricerca sul Cancro; Istituti di Ricerca e Cura a Carattere Scientifico Convenzione n. 152 Progetti Strategici Oncologia (Consiglio Nazionale delle Ricerche-Ministero dell'Istruzione, dell'Università e della Ricerca); and the European Union FP6, LSHC-CT-2003-503233, Selective Targeting of Angiogenesis and of Tumor Stroma.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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Note: E. Naumova is the recipient of a fellowship from the Monzino Foundation.
- Accepted December 19, 2005.
- Received July 27, 2005.
- Revision received December 5, 2005.