Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial.

Abstract

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.

• Authors: G N Hortobagyi, N T Ueno, W Xia, S Zhang, J K Wolf, J B Putnam, P L Weiden, J S Willey, M Carey, D L Branham, J Y Payne, S D Tucker, C Bartholomeusz, R G Kilbourn, R L De Jager, N Sneige, R L Katz, P Anklesaria, N K Ibrahim, J L Murray, R L Theriault, V Valero, D M Gershenson, M W Bevers, L Huang, G Lopez-Berestein, M C Hung
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 19 Issue 14 Pg. 3422-33 (Jul 15 2001) ISSN: 0732-183X [Print] United States
• PMID: 11454891 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenovirus E1A Proteins
• Cytokines
• Ki-67 Antigen
• Liposomes
• 3-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol
• Cholesterol

Topics

• Adenovirus E1A Proteins (genetics)
• Adult
• Aged
• Apoptosis
• Breast Neoplasms (genetics, metabolism, pathology, therapy)
• Cholesterol (analogs & derivatives)
• Cytokines (metabolism)
• Female
• Gene Expression
• Gene Transfer, Horizontal
• Genes, erbB-2
• Genetic Therapy
• Humans
• Immunohistochemistry
• In Situ Nick-End Labeling
• Injections
• Ki-67 Antigen
• Liposomes
• Middle Aged
• Ovarian Neoplasms (genetics, metabolism, pathology, therapy)
• Peritoneal Cavity
• Reverse Transcriptase Polymerase Chain Reaction
• Thorax
• Tumor Cells, Cultured