Systemic cancer gene therapy using adeno-associated virus type 1 vector expressing MDA-7/IL24.
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL24), selectively induces apoptosis in cancer cells without harming normal cells. It also exerts immunomodulatory and antiangiogenic effects, as well as potent antitumor bystander effects, making it an ideal candidate for a new anticancer gene therapy. Here, we examined the feasibility of adeno-associated virus type 1 (AAV1) vector-mediated systemic gene therapy using mda-7/IL24. In vitro studies showed that medium conditioned by AAV1-mda7-transducedC2C12 cells induces tumor cell-specific apoptosis and inhibits angiogenesis in a human umbilical vein endothelial cell tube formation assay. To assess the in vivo effects of AAV1-mediated systemic delivery of MDA-7/IL24, we generated a subcutaneous tumor model by injecting Ehrlich ascites tumor cells into the dorsum of DDY mice. A single intravenous injection of AAV1-mda7 (2.0 x 10(11) viral genomes) significantly inhibited tumor growth. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and immunohistochemical analyses showed significant induction of tumor-cell-specific apoptosis and reduction of microvessel formation within the tumors, and there was a significant increase in survival among the AAV1-mda7-treated mice. These results clearly demonstrate that continuous systemic delivery of MDA-7/IL24 can serve as an effective treatment for cancer. Thus, AAV1 vector-mediated systemic delivery of MDA-7/IL24 represents a potentially important new approach to anticancer therapy.
Tahara
Ichiro
I
Department of Biochemistry and Molecular Biology, Division of Gene Therapy Research, Center for Advanced Medical Technology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
Miyake
Koichi
K
Hanawa
Hideki
H
Kurai
Toshiyuki
T
Hirai
Yukihiko
Y
Ishizaki
Masamichi
M
Uchida
Eiji
E
Tajiri
Takashi
T
Shimada
Takashi
T
D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D017077:Culture Media, Conditioned; D017931:DNA Primers; D000229:Dependovirus / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D007378:Interleukins / Q000097:blood / Q000235:genetics*; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D000099180:Interleukin-24
D017077:Culture Media, Conditioned; D017931:DNA Primers; D007378:Interleukins; D000099180:Interleukin-24