PRECLINICAL AND CLINICAL-STUDY OF HER-2 NEU-TARGETING CANCER GENE-THERAPY/

Cationic liposomes have been used in many gene therapy approaches. The advantages of low toxicity, lack of immunological response, and easy preparation using cationic liposomes make multiple administrations pos sible, which may overcome the disadvantage of low transfection efficie ncy. Cationic liposomes, therefore, provide a promising procedure for delivering a therapeutic gene into cancer patients. Amplification or o verexpression of the HER-2/neu oncogene is frequently found in breast and ovarian cancers and correlates with poor clinical prognosis. We ha ve found that the adenovirus 5 EIA and the nontransforming simian viru s 40 (SV40) large-T antigen mutant can inhibit HER-2/neu overexpressio n and reverse the HER-2/neu-mediated malignant phenotypes. By using th e cationic liposome 3 N-(N',N'dimethylamino)ethanecarbamoyl]-cholester ol (DC-Chol), we successfully transferred E1A and/or large-T mutant in to established orthotopic breast and ovarian cancer models. The surviv al of a treated group of mice was significantly prolonged and the expr ession of HER-2/neu oncogene was down-regulated in vivo. A subsequent toxicity assay indicated that no significant toxicity was associated w ith the liposome-DNA complex administration even when we used ten time s the dose needed to achieve a therapeutic effect. Based on these data , a phase I clinical trial of DC-Chol-mediated EIA gene therapy for ov arian and breast cancers that overexpress HER-2/neu has been initiated in our institute. In this article, we will review the development of HER-2/neu-targeting gene therapy using cationic liposomes. (C) 1998 El sevier Science B.V.