Evaluation of endostatin antiangiogenesis gene therapy in vitro and in vivo.
Progressive growth and metastasis of solid tumors require angiogenesis, or the formation of new blood vessels. Endostatin is a 20-kDa carboxy-terminal fragment of collagen XVIII that has been shown to inhibit endothelial cell proliferation and tumor angiogenesis. Replication-deficient recombinant adenovirus (rAd) vectors were constructed, which encoded secreted forms of human and mouse endostatin (HECB and MECB, respectively), and, as a control, human alkaline phosphatase (APCB). Accumulation of endostatin was demonstrated in supernatants of cultured cells infected with the endostatin rAds. These supernatants disrupted tubule formation, inhibited migration and proliferation, and induced apoptosis in human dermal vascular endothelial cells or human vascular endothelial cells. Endostatin-containing supernatants had no effect on the proliferation of MidT2-1 mouse mammary tumor cells in vitro. A pharmacokinetic study of MECB in immunocompetent FVB mice demonstrated a 10-fold increase of serum endostatin concentrations 3 days after intravenous administration of 1x10(10) particles of this rAd (215-257 ng/mL compared to 12-38 ng/mL in control rAd-treated mice). Intravenous administration of MECB reduced b-FGF stimulated angiogenesis into Matrigel plugs by 38%. Intratumoral MECB inhibited growth of MidT2-1 syngeneic mammary tumors in FVB mice, but had minimal impact on the growth of MDA-MB-231 human breast tumors in SCID mice. Intravenous therapy with MECB also initially inhibited growth of MidT2-1 tumors, but this activity was subsequently blocked by induced anti-rAd antibodies. In summary, endostatin gene therapy effectively suppressed angiogenic processes in vitro and in vivo in several model systems.
Jin
X
X
Canji Inc., San Diego, California 92121, USA. xiaomei.jin@canji.com@
Bookstein
R
R
Wills
K
K
Avanzini
J
J
Tsai
V
V
LaFace
D
D
Terracina
G
G
Shi
B
B
Nielsen
L L
LL
D000256:Adenoviridae; D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics* / Q000627:therapeutic use; D043170:Collagen Type XVIII; D043169:Endostatins; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000628:therapy*; D010446:Peptide Fragments / Q000235:genetics* / Q000627:therapeutic use; D016865:Reassortant Viruses
D020533:Angiogenesis Inhibitors; D043170:Collagen Type XVIII; D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen