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 possible, which may overcome the disadvantage of low transfection efficiency. Cationic liposomes, therefore, provide a promising procedure for delivering a therapeutic gene into cancer patients. Amplification or overexpression of the HER-2/neu oncogene is frequently found in breast and ovarian cancers and correlates with poor clinical prognosis. We have found that the adenovirus 5 E1A and the nontransforming simian virus 40 (SV40) large-T antigen mutant can inhibit HER-2/neu overexpression and reverse the HER-2/neu-mediated malignant phenotypes. By using the cationic liposome 3beta[N-(N',N'dimethylamino)ethanecarbamoyl]-cholesterol (DC-Chol), we successfully transferred E1A and/or large-T mutant into established orthotopic breast and ovarian cancer models. The survival of a treated group of mice was significantly prolonged and the expression of HER-2/neu oncogene was down-regulated in vivo. A subsequent toxicity assay indicated that no significant toxicity was associated with the liposome-DNA complex administration even when we used ten times the dose needed to achieve a therapeutic effect. Based on these data, a phase I clinical trial of DC-Chol-mediated E1A gene therapy for ovarian 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.
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Department of Tumor Biology and Breast Cancer Basic Research Program, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
Yujiao Chang J
Hung
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