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Continuous Infusion of Endostatin Inhibits Differentiation, Mobilization, and Clonogenic Potential of Endothelial Cell Progenitors¹

Division of Hematology-Oncology, Department of Medicine [P. M., C. D., G. M., F. B.], Department of Experimental Oncology-IFOM/Fondazione Italiana Ricerca sul Cancro Institute of Molecular Oncology [M. C., A. G., S. M.], and Department of Pathology-Laboratory Medicine [G. P.], European Institute of Oncology, 20141 Milan, Italy, and The Jackson Laboratory, Bar Harbor, Maine 04609 [L. S.]

Purpose: We investigated the effect of endostatin on differentiation, mobilization, and clonogenic potential of circulating endothelial cell (EC) progenitors, and whether the effect of endostatin was improved by continuous infusion (CI) versus bolus administration.

Experimental Design: Four-color flow cytometry and clonogenic EC cultures were used to study EC progenitors in tumor-free mice, tumor-bearing immunodeficient mice, and immunodeficient mice xenotransplanted with human bone marrow (BM) cells.

Results: Endostatin significantly reduced the number of circulating EC progenitors in tumor-free BALB/c mice. The effect of endostatin on EC progenitors was enhanced significantly in mice treated with CI drug treatment. When immunodeficient mice xenotransplanted with human BM cells were treated with CI of endostatin we observed a significant decrease in the engraftment and differentiation of human BM-derived EC progenitors. Numbers of circulating EC progenitors increased 7-fold in immunodeficient mice bearing human lymphoma. In this preclinical model, treatment with CI of endostatin inhibited host murine EC progenitor mobilization and human tumor growth. Furthermore, the clonogenic potential of EC progenitors was impaired severely.

Conclusions: Endostatin is a potent inhibitor of the mobilization and clonogenic potential of human and murine EC progenitors, and its preclinical activity is increased significantly in CI compared with bolus administration. These observations might be useful in the design of future clinical trials.

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