Adenoviral-mediated gene therapy of human bladder cancer with antisense interleukin-8.
We previously demonstrated the importance of interleukin-8 (IL-8) as a mediator of angiogenesis, tumorigenicity, and metastasis of transitional cell carcinoma (TCC) of the bladder. In the present study, we evaluated the feasibility of adenoviral mediated antisense IL-8 gene transfer (Ad IL-8-AS) as therapy for established TCC. In vitro, Ad IL-8-AS inhibited endothelial cell proliferation and enhanced endothelial cell apoptosis. The highly metastatic human TCC cell line 253J B-V(R) was implanted into the subcutis of athymic nude mice, and intralesional therapy with Ad IL-8-AS commenced when the tumors reached a diameter between 5 and 7 mm. Tumor growth was significantly inhibited compared with therapy in controls (saline and beta-galactosidase adenovirus). Ad IL-8-AS therapy decreased the in vivo expression of IL-8 and matrix metalloproteinase type 9 (MMP-9), reduced microvessel density, and enhanced endothelial cell apoptosis. These results indicate that Ad IL-8-AS therapy targets both tumor cells and host endothelial cells resulting in endothelial cell apoptosis and significant inhibition of tumor growth.
Inoue
K
K
Department of Cancer Biology, The University of Texas M.D Anderson Cancer Center, Houston, TX 77030, USA.
Wood
C G
CG
Slaton
J W
JW
Karashima
T
T
Sweeney
P
P
Dinney
C P
CP
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D001616:beta-Galactosidase / Q000378:metabolism
D016375:Antisense Elements (Genetics); D017931:DNA Primers; D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D001616:beta-Galactosidase; D020780:Matrix Metalloproteinase 9