P53 TUMOR-SUPPRESSOR GENE-THERAPY FOR CANCER

The last two decades have led to a greater understanding of the geneti c basis of human malignancy. Although numerous genetic alterations hav e been detected in cancer, activation of oncogenes and inactivation of cell cycle regulators (e.g., tumor suppressor genes) are now known to play a critical role in the progression of the disease. Therapeutic s trategies based on specific molecular alterations in cancer include re introduction of wild-type tumor suppressor function to cells lacking t he gene. p53 gene therapy provides an attractive strategy to test the potential clinical feasibility of this approach. Alterations in p53 fu nction are present in approximately half of all malignancies, and expr ession of wild-type p53 can result in apoptosis in human tumor cells. This review summarizes current investigations with p53 gene therapy, h ighlighting the preclinical efforts with adenoviral, retroviral, and l ipid-based gene delivery systems. A comprehensive review of the variou s clinical targets suggested for p53 gene therapy is presented togethe r with challenges and prospects for future clinical investigation.