Tumor-targeted p53-gene therapy enhances the efficacy of conventional chemo/radiotherapy

A long-standing goal in gene therapy for cancer is a stable, low toxic, sys temic gene delivery system that selectively targets tumor cells, including metastatic disease. Progress has been made toward developing non-viral, pha rmaceutical formulations of genes for in vivo human therapy, particularly c ationic liposome-mediated gene transfer systems. Ligand-directed tumor targ eting of cationic liposome-DNA complexes (lipoplexes) is showing promise fo r targeted gene delivery and systemic gene therapy. Lipoplexes directed by ligands such as folate, transferrin or anti-transferrin receptor scFv, show ed tumor-targeted gene delivery and expression in human breast, prostate, h ead and neck cancers. The two elements, ligand/receptor and liposome compos ition, work together to realize the goal of functional tumor targeting of g ene therapeutics. The tumor suppressor gene, p53, has been shown to be invo lved in the control of DNA damage-induced apoptosis. Loss or malfunction of this p53-mediated apoptotic pathway has been proposed as one mechanism by which tumors become resistant to chemotherapy or radiation. The systemicall y delivered ligand-liposome-p53 gene therapeutics resulted in efficient exp ression of functional wild-type p53, sensitizing the tumors to chemotherapy and radiotherapy. This is a novel strategy combining current molecular med icine with conventional chemotherapy and radiotherapy for the treatment of cancer. The systemic delivery of normal tumor suppressor gene p53 by a non- viral, tumor-targeted delivery system as a new therapeutic intervention has the potential to critically impact the clinical management of cancer. (C) 2001 Elsevier Science B.V. All rights reserved.