Gene therapy that safely targets and kills tumor cells throughout the body
D. Meruelo, J. Tseng, A. Hurtado, B. Levin, C. Pampeno
NYU School of Medicine, Department of Pathology, 550 First Avenue, New York, NY 10016, USA
We studied the therapeutic value of Sindbis vectors for advanced
metastatic cancer by using a variety of clinically accurate mouse
models and have demonstrate through imaging, histologic, and molecular
data that Sindbis vectors systemically and specifically infect/detect
and kill metastasized tumors in vivo, leading to significant
suppression of tumor growth and enhanced survival. Use of two different
bioluminescent genetic markers for the IVIS Imaging System permitted
demonstration of an excellent correlation between vector delivery and
metastatic locations in vivo. Sindbis tumor specificity is not
attributable to a species difference between human tumor and mouse
normal cells. Sindbis virus is known to infect mammalian cells using
the Mr 67,000 laminin receptor. Immunohistochemical staining of tumor
cells indicates that laminin receptor is elevated in tumor versus
normal cells. Down-regulated expression of laminin receptor with small
interfering RNA significantly reduces the infectivity of Sindbis
vectors. Tumor overexpression of the laminin receptor may explain the
specificity and efficacy that Sindbis vectors demonstrate for tumor
cells in vivo. We show that incorporation of antitumor cytokine genes
such as interleukin-12 and interleukin-15 genes enhances the efficacy
of the vector. These results suggest that Sindbis viral vectors may be
promising agents for both specific detection and growth suppression of
metastatic ovarian cancer.
Key words:
Sindbis vectors gene therapy in vivo tumors
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