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The Vascular Targeting Property of Paclitaxel Is Enhanced by SU6668, a Receptor Tyrosine Kinase Inhibitor, Causing Apoptosis of Endothelial Cells and Inhibition of Angiogenesis

Authors' Affiliations: ¹ Laboratory of Biology and Treatment of Metastasis, Department of Oncology, "Mario Negri" Institute for Pharmacological Research, Bergamo, Italy; ² Laboratory of Cancer Pharmacology, Department of Oncology, "Mario Negri" Institute for Pharmacological Research, Milan, Italy; ³ Laboratory of Immunology and Genetics of Rare Diseases and Transplantation, Department of Molecular Medicine, "Mario Negri" Institute for Pharmacological Research, Ranica, Italy; ⁴ Section of Veterinary Pathology, Department of Animal Pathology, Hygiene, and Public Health, University of Milan; and ⁵ Tumour Biology and Metastasis, Cancer Research UK Centre for Cancer Therapeutics, McElwain Laboratories, Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: Raffaella Giavazzi, Laboratory of Biology and Therapy of Metastasis, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125 Bergamo, Italy. Phone: 39-035-319-888; Fax: 39-035-319-331; E-mail: giavazzi{at}marionegri.it.

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.