Combination angiostatin and endostatin gene transfer induces synergistic antiangiogenic activity in vitro and antitumor efficacy in leukemia and solid tumors in mice.
Angiostatin and endostatin are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vivo and tumor growth in mice. However, tumor shrinkage requires chronic delivery of large doses of these proteins. Here we report synergistic antitumor activity and survival of animals when these factors are delivered in combination to tumors by retroviral gene transfer. We have demonstrated this efficacy in both murine leukemia and melanoma models. Complete loss of tumorigenicity was seen in 40% of the animals receiving tumors transduced by the combination of angiostatin and endostatin in the leukemia model. The synergy was also demonstrated in vitro on human umbilical vein endothelial cell differentiation and this antiangiogenic activity may suggest a mechanism for the antitumor activity in vivo. These findings imply separate pathways by which angiostatin and endostatin mediate their antiangiogenic effects. Together, these data suggest that a combination of antiangiogenic factors delivered by retroviral gene transfer may produce synergistic antitumor effects in both leukemia and solid tumors, thus avoiding long-term administration of recombinant proteins. The data also suggest that novel combinations of antiangiogenic factors delivered into tumors require further investigation as therapeutic modalities.
Department of Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
F A
FA
Scappaticci
R
R
Smith
A
A
Pathak
D
D
Schloss
B
B
Lum
Y
Y
Cao
F
F
Johnson
E G
EG
Engleman
G P
GP
Nolan
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival; D003094:Collagen / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D015536:Down-Regulation; D004338:Drug Combinations; D043169:Endostatins; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D007938:Leukemia / Q000628:therapy*; D008164:Luminescent Proteins / Q000378:metabolism; D008545:Melanoma / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008957:Models, Genetic; D008979:Moloney murine leukemia virus / Q000235:genetics; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D010958:Plasminogen / Q000008:administration & dosage / Q000627:therapeutic use*; D011233:Precipitin Tests; D011509:Proteoglycans / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D043169:Endostatins; D007797:Laminin; D008164:Luminescent Proteins; D010446:Peptide Fragments; D011509:Proteoglycans; C059485:matrigel; D049452:Green Fluorescent Proteins; D043168:Angiostatins; D010958:Plasminogen; D003094:Collagen