Endostatin therapy reveals a U-shaped curve for antitumor activity.
Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.
Tjin Tham Sjin
R M
RM
Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Naspinski
J
J
Birsner
A E
AE
Li
C
C
Chan
R
R
Lo
K-M
KM
Gillies
S
S
Zurakowski
D
D
Folkman
J
J
Samulski
J
J
Javaherian
K
K
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D043169:Endostatins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D016415:Sequence Alignment
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D043169:Endostatins