Continuous intravascular secretion of endostatin in mice from transduced hematopoietic stem cells.
Endostatin, a 20-kDa carboxy-terminal fragment of collagen XVIII, is the leading member of a class of physiologic inhibitors of angiogenesis with potent antitumor activity. Repeated subcutaneous administration of recombinant endostatin in mice led to permanent regression of established tumors to a microscopic dormant state and prompted the initiation of human clinical trials. However, a discrepancy remained unresolved: sustained tumor regression has only been observed with a non-soluble, precipitated form of recombinant endostatin produced in bacteria. To shed light on this question and establish a model of systemic anti-angiogenic gene therapy of cancer that may surmount obstacles in protein production and delivery, we transduced murine hematopoietic stem cells with a retrovirus encoding a secretable form of endostatin. Despite continuous, high-level secretion of endostatin in the vasculature of all transplanted mice, we detected neither inhibition of in vivo neoangiogenesis nor antitumor activity. Resolution of this paradox may come from human trials of endostatin now underway.
Pawliuk
Robert
R
Division of Health Sciences & Technology, Harvard-MIT, Cambridge, Massachusetts 02139, USA.
Bachelot
Thomas
T
Zurkiya
Omar
O
Eriksson
Anna
A
Cao
Yihai
Y
Leboulch
Philippe
P
D020533:Angiogenesis Inhibitors; D000818:Animals; D016026:Bone Marrow Transplantation; D003094:Collagen / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D043170:Collagen Type XVIII; D003315:Cornea / Q000098:blood supply; D043169:Endostatins; D005354:Fibrosarcoma / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D003094:Collagen