Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin.
OBJECTIVE
Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo.


METHODS
We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model.


RESULTS
We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor.


CONCLUSIONS
These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.
Kikuchi
Eiji
E
Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Menendez
Silvia
S
Ohori
Makoto
M
Cordon-Cardo
Carlos
C
Kasahara
Noriyuki
N
Bochner
Bernard H
BH
D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D043169:Endostatins / Q000235:genetics* / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D016086:Lentivirus / Q000235:genetics*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms / Q000473:pathology*
D043169:Endostatins; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins