Abstract
Background
Resistance to radiation and chemotherapy is a significant obstacle to the treatment of advanced bladder cancer. Gene therapy combined with radiation represents a new approach to cancer treatment. In the present study, we investigated whether adenovirally directed, cytosine deaminase (CD)/5‐fluorocytosine (5‐FC) gene therapy could induce cell toxicity and radiosensitization through the intracellular production of 5‐fluorouracil (5‐FU) in bladder‐cancer cells.
Methods
Three human bladder‐cancer cell lines, KK47 (wild‐type p53+), T24 (p53 mutated) and 5637 (p53 mutated), were investigated. A recombinant adenovirus vector containing the CD gene (Ad‐RSV‐CD) was used. Cells were infected with Ad‐RSV‐CD and treated with 5‐FC. Forty‐eight hours after infection, the cells were irradiated and cytotoxicity assays performed to determine the extent of increase in in vitro cytotoxicity. A KK47 subcutaneous tumor‐xenografts model was used in an animal study to examine the tumor growth inhibitory effect of this combination therapy. Ad‐RSV‐CD was directly injected into the tumor and daily 5‐FC was intraperitoneally injected. Forty‐eight hours after injection of Ad‐RSV‐CD, the tumor was irradiated. The tumor volume was measured every day.
Results
In all three cell lines, the combination treatment enhanced the cell killing of human bladder‐cancer cells in vitro. It also enhanced the tumor‐growth inhibition in the KK47 tumor model.
Conclusions
In the present study, we demonstrated that CD/5‐FC gene therapy combined with radiation therapy enhances cell killing of human bladder‐cancer cells in in vitro and in vivo animal models. Copyright © 2003 John Wiley & Sons, Ltd.