Adenovirus-mediated gene therapy for bladder cancer: efficient gene delivery to normal and malignant human urothelial cells in vitro and ex vivo.
Existing local therapies for superficial transitional cell carcinoma (TCC) of the bladder have limited success in preventing progression to life-threatening, muscle-invasive disease, and novel therapies are needed. Recent studies have raised doubts concerning the feasibility of adenovirus-mediated gene therapy for bladder cancer. We have therefore investigated adenoviral transduction of normal and malignant human urothelial cells, both as primary cultures and in intact epithelium. All 15 primary normal human urothelial cell lines tested were transduced in vitro by Adv-cmv-beta-gal at high efficiency, and better than most human TCC cell lines. Eight primary human TCC explants were also successfully transduced. In contrast, in intact normal urothelium, transduction efficiency was lower, and occurred only in superficial epithelial layers. Expression of the hCAR adenovirus receptor, however, occurred throughout the full thickness of urothelium. Transduction of human TCC biopsy specimens was at least as efficient as intact normal urothelium.We demonstrate for the first time that adenoviral transduction of both normal and malignant human urothelial cells is feasible. A physical barrier, rather than hCAR status, may be the main determinant of transduction of intact epithelium. Clinical trials of adenovirus-mediated gene therapy for superficial bladder cancer are warranted.
Chester
J D
JD
Cancer Research UK Clinical Centre in Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Kennedy
W
W
Hall
G D
GD
Selby
P J
PJ
Knowles
M A
MA
D000260:Adenoviruses, Human / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000628:therapy*; D002478:Cells, Cultured; D004492:Edetic Acid; D005455:Fluorescent Antibody Technique; D018390:Gene Targeting / Q000379:methods; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D014161:Transduction, Genetic / Q000379:methods*; D014357:Trypsin; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000628:therapy*; D019459:Urothelium / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics
D004492:Edetic Acid; D001616:beta-Galactosidase; D014357:Trypsin