Regulatory sequences of the H19 gene in DNA basedtherapy of bladder cancer

摘要

The objective of the present study was to develop novel DNA based therapy strategies for bladder cancer. We detected a high expression level of the H19 gene in murine and human bladder carcinoma tissues compared to nearly undetectable levels in the surrounding normal tissues. On the basis of these findings we constructed a plasmid in which H19 regulatory sequences drove the expression of the diphtheria toxin A gene. This plasmid was introduced by intravesical instillation into the bladders of rats with bladder carcinoma (orthotopic model) and into the bladders of two human patients suffering recurrent superficial transitional cell carcinoma, refractory to all commonly used treatments. Very significant tumor growth inhibition was observed in the rat bladder tumors after two intravesical injections of 50 μg of DTA-H19 toxin vector as compared to control animals. Nearly complete ablation of the tumor was determined by video imaging in the two human patients after treating once a week with 2 mg of DTA-H19 plasmid for a total of 9 weeks. Not even a trace of the plasmid could be detected in the bloodstream of the patients. This observation strongly indicates the safety of our treatment. These observations may be the first step of a major breakthrough in the treatment of human bladder carcinoma.