Status and prospects of gene therapy for urologic cancer.

SINCE THE FIRST APPROVED CLINICAL PROTOCOL for somatic gene therapy in patients with adenosine deaminase deficiency started in 1990, approximately 400 clinical protocols, mainly for malignant diseases, have been approved worldwide. In Japan, however, only two clinical studies on cancer gene therapy—immunotherapy for renal cell carcinoma using granulocyte-monocyte colony stimulating factor (GM-CSF) and gene replacement therapy using an adenovirus-p53 for lung cancer—are currently being conducted. Recently, three new clinical protocols have been approved, and three protocols, including “suicide gene” therapy using an adenovirus-herpes simplex virus thymidine kinase gene (HSV-tk) and ganciclovir (GCV) for prostate cancer, are being reviewed by the Japanese National Committee for Gene Therapy. Although the number of clinical protocols in Japan is still small, fundamental research is reaching high levels of excellence. There is an increasing need for our urologists to have an understanding of the basic concepts of gene therapy, its potential applications, and its shortcomings. Accordingly, we founded the Japanese Society for Urological Gene Therapy in 1999 in order to stimulate communication and collaboration with other physicians and basic scientists. The first meeting was held on November 20th, 1999, in Okayama. Two guest speakers, Prof. Asano, Director of the Research Hospital, Institute of Medical Science, at the University of Tokyo, and Dr. Fujiwara, Department of Surgery, Okayama University Medical School, and seven active urologists outlined the status of and prospects for gene therapy for urologic cancer. As Prof. Asano explains in this issue, current gene therapy is regarded as translational research from the bench to the bedside, which must go back to the bench after the clinical data have been reviewed. The main problems are still the failure of vectors to transduce efficiently in vivo and the incomplete understanding of the molecular pathology of tumor development and progression. In this early stage of the technology, urogenital organs are excellent targets for the application and evaluation of gene therapy. For example, because conventional cytokine therapy and adoptive immunotherapy are clearly effective against renal-cell carcinoma, it is very suitable to incorporate their use for immune gene therapy by means of cytokine gene transfer and tumor cell vaccination. Bladder tumors have shown excellent responses to intravesically administered immune response modifiers such as interferon and bacillus Calmette-Guerin. Intravesical administration is a simple and reliable way to deliver the genetic agent, and cystoscopy and urinary cytology will be helpful in evaluating the response of the tumor to treatment. For prostate cancer, direct intratumoral injection under ultrasonographic guidance is also a simple and effective way to deliver the genetic agent, and prostate-specific antigen (PSA) is an extremely sensitive marker for therapeutic effectiveness. Basic strategies that have been studied for clinical gene therapy include immune therapy using cytokine gene transfer and tumor cell vaccination, replacement therapy using tumor suppressor genes, antisense therapy to inhibit activated oncogenes, and suicide gene therapy activating selective prodrugs. All four of these strategies already have been applied to urologic cancers, presenting an acceptable safety profile but with limited clinical benefits and many hurdles to be overcome. A number of promising new approaches to circumvent obstacles encountered in the attempt to realize successful gene therapy are being investigated in preclinical and clinical studies. Ex vivo gene transfer is an important strategy for immune gene therapy. The present situation of GM-CSF-transduced tumor vaccines for renal-cell carcinoma and prostate cancer is reviewed by Kawai and associates, making reference to the more recent development of allogenic vaccinations. Other tumor vaccine technology employs viruses or packaged segments of DNA that deliver the cytokine gene directly into the malignant cells by intratumor injection. Similarly, plasmid DNA vectors (naked DNA) can be transferred in vivo, and Nishitani and colleagues discuss cancer vaccination therapy by gene gun-mediated transfection of the interleukin-12 gene. Tumorigenesis is a complex, multistep pathway involving many gene defects associated with cell-cycle regulation, angiogenesis, immunoreactivity, and cell adhesion. Therefore, it is very difficult to select the most potent target for tumor suppressor therapy and oncogene inactivation. One of the most promising approaches to restore programmed cell death in tumor cells is replacement of the p53 gene; p53 gene therapy alone or combined with radiation or chemotherapy has been used in the treatment of various cancers, including bladder and prostate cancers. Dr. Fujiwara is one of the pioneers in developing p53 gene therapy, and his present comprehensive review