Anti-tumor efficacy of human angiostatin using liver-mediated adeno-associated virus gene therapy.
Angiostatin is a potent endogenous inhibitor of angiogenesis and tumor growth in vivo. The therapeutic potential of adeno-associated viral (AAV) gene delivery of angiostatin in modulating tumor growth in vivo was evaluated. Sustained levels of angiostatin were detected in the sera of mice for up to 6 months after they received a single injection of AAV-angiostatin. AAV-mediated stable expression of angiostatin inhibited tumor burden in the highly aggressive B16F10 melanoma and Lewis lung carcinoma (LLC) models of experimental metastasis. Moreover, AAV-angiostatin prolonged survival in B16F10 and LLC tumor-bearing mice compared to control groups. Anti-tumor efficacy was consistently observed when angiostatin serum levels of 15-50 ng/ml were detected following gene transfer, but the effect was minimal when the levels were lower or higher than this range. The combination of AAV-angiostatin gene therapy with chemotherapy was also shown to extend marginally the survival of mice bearing preestablished human tumors; however, the effect was evident only within a narrow dose of circulating angiostatin. These studies demonstrate the feasibility of using AAV anti-angiogenic gene therapy as a cancer treatment modality and suggest that the optimal anti-tumor efficacy of angiostatin following gene transfer may be limited to a narrow dose range.
Lalani
Alshad S
AS
Cell Genesys, Inc., South San Francisco, California 94080, USA.
Chang
Betty
B
Lin
JianMin
J
Case
Scott S
SS
Luan
Bo
B
Wu-Prior
Wei-Wei
WW
VanRoey
Melinda
M
Jooss
Karin
K
D020533:Angiogenesis Inhibitors / Q000235:genetics* / Q000378:metabolism; D043168:Angiostatins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D002642:Chick Embryo; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008099:Liver / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000235:genetics / Q000628:therapy*; D014161:Transduction, Genetic
D020533:Angiogenesis Inhibitors; D043168:Angiostatins