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Cationic Liposome-Mediated E1A Gene Transfer to Human Breast and Ovarian Cancer Cells and Its Biologic Effects: A Phase I Clinical Trial

From the Departments of Breast Medical Oncology, Molecular and Cellular Oncology, Blood and Marrow Transplantation, Gynecological Oncology, Thoracic Surgery, Pathology, and Bioimmunotherapy, and Section of Immunobiology and Drug Carriers, The University of Texas M.D. Anderson Cancer Center, Houston; RGene Therapeutics, Inc, Woodlands, TX; Department of Internal Medicine, Medical Oncology, Rush-Presbyterian St Luke’s Medical Center, Chicago, IL; Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and Section of Hematology/Oncology, Virginia Mason Medical Center, and Targeted Genetics Corp, Seattle, WA.

Address reprint requests to Gabriel N. Hortobagyi, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 56, Houston, TX 77030; email: ghorto{at}notes.mdacc.tmc.edu

PURPOSE: Preclinical studies have demonstrated that the adenovirus type 5 E1A gene is associated with antitumor activities by transcriptional repression of HER-2/neu and induction of apoptosis. Indeed, E1A gene therapy is known to induce regression of HER-2/neu–overexpressing breast and ovarian cancers in nude mice. Therefore, we evaluated the feasibility of intracavitary injection of E1A gene complexed with DC-Chol cationic liposome (DCC-E1A) in patients with both HER-2/neu–overexpressing and low HER-2/neu–expressing breast and ovarian cancers in a phase I clinical trial.

PATIENTS AND METHODS: An E1A gene complexed with DCC-E1A cationic liposome was injected once a week into the thoracic or peritoneal cavity of 18 patients with advanced cancer of the breast (n = 6) or ovary (n = 12).

RESULTS: E1A gene expression in tumor cells was detected by immunohistochemical staining and reverse transcriptase–polymerase chain reaction. This E1A gene expression was accompanied by HER-2/neu downregulation, increased apoptosis, and reduced proliferation. The most common treatment-related toxicities were fever, nausea, vomiting, and/or discomfort at the injection sites.

CONCLUSION: These results argue for the feasibility of intracavitary DCC-E1A administration, provide a clear proof of preclinical concept, and warrant phase II trials to determine the antitumor activity of the E1A gene.

M.C.H. is a paid consultant of and owns stock in Targeted Genetic Corporation.

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