Strategies for prostate cancer gene therapy

Gene therapy for prostate cancer is a relatively new experimental treatment modality and several different therapeutic approaches are being considered. Prostate cancer is the most commonly diagnosed cancer in males and has unique features that make it ideal for gene therapy. Although prostate cancer that is confined to the gland can be cured in many of the patients using local treatments (radical prostatectomy or irradiation therapy), the long-term failure rate of these therapies suggests that cancers can metastasize relatively early in the course of the disease. Once prostate cancer has metastasized there are no curative therapies. The greatest challenge in the treatment of advanced prostate cancer is to access and eliminate metastatic cells. Therefore, successful prostate cancer gene therapy will ultimately require an effective strategy to kill cancer cells both at the site of the primary tumor and at distant metastatic sites. In this article we review many aspects of gene therapy specifically relevant for prostate cancer. We discuss the unique advantages and disadvantages of nonviral and viral gene delivery systems. Evidence that gene delivery directly into tumors, in situ, is effective for prostate cancer is presented. We provide a broad review of three general approaches or strategies for prostate cancer gene therapy: Corrective, cytoreductive, and immunomodulatory gene therapy. Replacement of the tumor suppressor gene p53 is the best studied example of corrective gene therapy. The cytoreductive gene therapy that has been used most extensively is herpes simplex virus thymidine kinase (HSV-tk) combined with the prodrug ganciclovir. Immunomodulatory gene therapy approaches such as enhancement of cancer cell recognition, e.g. with antigen encoded gene vaccine approaches, and augmentation of the cellular immune response with specific immunomodulatory molecules such as interleukin-12 have the potential to effectively treat both local prostate cancer and distant metastases.