Enhancement of antitumor activity of gammaretrovirus carrying IL-12 gene through genetic modification of envelope targeting HER2 receptor: a promising strategy for bladder cancer therapy.
The objective of this study was to develop an HER2-targeted, envelope-modified Moloney murine leukemia virus (MoMLV)-based gammaretroviral vector carrying interleukin (IL)-12 gene for bladder cancer therapy. It displayed a chimeric envelope protein containing a single-chain variable fragment (scFv) antibody to the HER2 receptor and carried the mouse IL-12 gene. The fragment of anti-erbB2scFv was constructed into the proline-rich region of the viral envelope of the packaging vector lacking a transmembrane subunit of the carboxyl terminal region of surface subunit. As compared with envelope-unmodified gammaretroviruses, envelope-modified ones had extended viral tropism to human HER2-expressing bladder cancer cell lines, induced apoptosis, and affected cell cycle progression despite lower viral titers. Moreover, animal studies showed that envelope-modified gammaretroviruses carrying IL-12 gene exerted higher antitumor activity in terms of retarding tumor growth and prolonging the survival of tumor-bearing mice than unmodified ones, which were associated with enhanced tumor cell apoptosis as well as increased intratumoral levels of IL-12, interferon-gamma, IL-1beta, and tumor necrosis factor-alpha proteins. Therefore, the antitumor activity of gammaretroviruses carrying the IL-12 gene was enhanced through genetic modification of the envelope targeting HER2 receptor, which may be a promising strategy for bladder cancer therapy.
Tsai
Y-S
YS
Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan.
Shiau
A-L
AL
Chen
Y-F
YF
Tsai
H-T
HT
Tzai
T-S
TS
Wu
C-L
CL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008979:Moloney murine leukemia virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D014161:Transduction, Genetic; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000628:therapy* / Q000821:virology*; D056189:Viral Tropism
D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human