Continuous infusion of endostatin inhibits differentiation, mobilization, and clonogenic potential of endothelial cell progenitors.
OBJECTIVE
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.


METHODS
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.
Capillo
Manuela
M
Department of Medicine, European Institute of Oncology, 20141 Milan, Italy.
Mancuso
Patrizia
P
Gobbi
Alberto
A
Monestiroli
Silvia
S
Pruneri
Giancarlo
G
Dell'Agnola
Chiara
C
Martinelli
Giovanni
G
Shultz
Leonard
L
Bertolini
Francesco
F
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use*; D013234:Stem Cells; D013997:Time Factors
D000970:Antineoplastic Agents; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen