New cancer therapy using genetically-engineered oncolytic Sendai virus vector.
We have developed a new type of Sendai virus-(SeV) based gene transfer vectors for cancer therapy. The matrix gene-, indispensable for particle formation, deficient and fusion gene-, essential for cell-fusion and deciding viral tropism, redesigned SeV vector loses vector particle formation from transduced cells and gains cell-to-cell spreading in protease-dependent, namely controllable, manner. For the selective delivery to malignant tumor cells expressing matrix metalloproteinases (MMPs) or urokinase-type plasminogen activator (uPA), we introduced MMP-cleavage (PLGMTS) or uPA-cleavage (SGRS) sequences, respectively, immediately prior to the cleavage site for activation of fusion protein with remaining essential sequences for cell-fusion. The MMP-targeted SeV vector demonstrated syncytia formation in MMP expressing HT1080 cell line in vitro, and growth inhibition of HT1080 subcutaneous xenografts in vivo. The uPA-targeted one showed the same effects in uPA expressing PC-3 cell line. Severe apoptosis occurred in fused-cells. Thus, the vector selectively spreads to tumor cells in tumor-protease dependent manner and demonstrates the antitumor effects in solid tumors, indicating the value of selective targeting and killing of tumors by recombinant SeV technology.
Kinoh
Hiroaki
H
DNAVEC Corporation, 1-25-11 Kannondai, Tsukuba-shi, Ibaraki 305-0856, Japan.
Inoue
Makoto
M
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005818:Genetic Engineering / Q000379:methods*; D015316:Genetic Therapy / Q000295:instrumentation / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D050504:Oncolytic Viruses / Q000235:genetics; D029082:Sendai virus / Q000235:genetics*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D014568:Urokinase-Type Plasminogen Activator; D020782:Matrix Metalloproteinases