Induction of therapeutic antitumor antiangiogenesis by intratumoral injection of genetically engineered endostatin-producing Semliki Forest virus.
Antiangiogenic therapy using Semliki Forest virus (SFV) carrying Endostatin gene for malignant brain tumor was investigated to improve the therapeutic efficacy. The efficiency of SFV-mediated gene delivery was first evaluated for B 16 cells and compared with the efficiency in cells of endothelial origin (HMVECs). HMVECs are more susceptible to SFV infection than B 16 cells. For the in vivo treatment model, phosphate-buffered saline, SFV-LacZ, retrovirus vector GCsap-Endostatin, and SFV-Endostatin were injected to mice bearing B 16 brain tumors. A very significant inhibition of tumor growth was observed in the group that had been treated with SFV-Endostatin. A marked reduction of intratumoral vascularization was seen in the tumor sections from the SFV-Endostatin group compared with tumor sections from the SFV-LacZ or GCsap-Endostatin groups. Moreover, at day 7 after intravenous administration of SFV-Endostatin, the serum level of endostatin was augmented more than 3-fold compared to that after intravenous administration of GCsap-Endostatin. The results indicated that treatment with SFV-Endostatin inhibited the angiogenesis with established tumors. Gene therapy with Endostatin delivered via SFV may be a candidate for the development of new therapy for brain tumors.
Yamanaka
R
R
Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. ryaman@pop11.odn.ne.jp
Zullo
S A
SA
Ramsey
J
J
Onodera
M
M
Tanaka
R
R
Blaese
M
M
Xanthopoulos
K G
KG
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000628:therapy* / Q000821:virology; D002478:Cells, Cultured; D003094:Collagen / Q000097:blood / Q000235:genetics*; D043169:Endostatins; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000821:virology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply / Q000628:therapy* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy*; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000502:physiology*; D015996:Survival Rate
D043169:Endostatins; D010446:Peptide Fragments; D003094:Collagen