Using sindbis viral vectors for specific detection and suppression of advanced ovarian cancer in animal models.
We studied the therapeutic value of Sindbis vectors for advanced metastatic ovarian cancer by using two highly reproducible and clinically accurate mouse models: a SCID xenograft model, established by i.p. inoculation of human ES-2 ovarian cancer cells, and a syngenic C57BL/6 model, established by i.p. inoculation of mouse MOSEC ovarian cancer cells. We demonstrate through imaging, histologic, and molecular data that Sindbis vectors systemically and specifically infect/detect and kill metastasized tumors in the peritoneal cavity, leading to significant suppression of the carcinomatosis in both animal models. Use of two different bioluminescent genetic markers for the IVIS Imaging System permitted demonstration, for the first time, of an excellent correlation between vector delivery and metastatic locations in vivo. Sindbis vector infection and growth suppression of murine MOSEC tumor cells indicate that 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.
Tseng
Jen-Chieh
JC
New York University Cancer Institute, the Rita J. and Stanley H. Kaplan Comprehensive Cancer Center, and the New York University Gene Therapy Center, New York University School of Medicine, New York, New York 10016, USA.
Hurtado
Alicia
A
Yee
Herman
H
Levin
Brandi
B
Boivin
Christopher
C
Benet
Marta
M
Blank
Stephanie V
SV
Pellicer
Angel
A
Meruelo
Daniel
D
D000818:Animals; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008163:Luminescent Measurements; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy / Q000821:virology*; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D017474:Receptors, Laminin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012845:Sindbis Virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D017474:Receptors, Laminin