Clonal development of bladder cancer and its relevance to the clinical potential of HLA antigen and TP53 based gene therapy.

In the last decade there has been major progress in understanding the multiple steps involved in cancer cells developing their malignant potential. Study of bladder cancer has provided important information during this period and helped to identify HLA class I and wild type normal TP53 as potential probes for gene therapy studies. Given the magnitude of genetic damage that is associated with the clonal development of bladder cancer, and particularly the number of cellular mechanisms that have been highjacked in the development of terminal metastatic disease, it is obviously highly unlikely that a single gene therapy involving HLA class I alone would work in terminal metastatic disease. However, it seems possible that HLA-B7 treatment of patients with bladder cancer who are candidates for salvage cystectomy would benefit such patients. If it were to work, it could provide a whole new approach to managing superficial tumours. However for patients with extensive metastatic disease, progress could come from investing more effort in uncoverinlg the genetic basis of the chemosensitivity of germ cell tumours and understanding the basis of the normal checkpoints of meiosis and the role of TP53. This could provide a completely new approach to gene therapy that might be exploited even in patients with advanced metastatic disease. Such a tetraploidal construct combined with allogeneic HLA class I and incorporated into a low pathogenic lytic viral construct to induce oncolysis with some form of tissue promoter to focus the cell types in which the genes will be activated could provide ideal effective gene therapy.