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Systemic Gene Therapy in Human Xenograft Tumor Models by Liposomal Delivery of the E1A Gene¹

Breast Cancer Research Program Core Laboratory [N. T. U., C. B.], and Departments of Blood and Marrow Transplantation [N. T. U., C. B.], Molecular and Cellular Oncology [N. T. U., C. B., W. X., M-C. H.], and Surgical Oncology [M-C. H.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Targeted Genetics Corporation, Seattle, Washington 98101 [P. A., E. M. B., E. M., R. P.]; Center for Pharmacogenetics, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [S. L., L. H.]; and Department of Otolaryngology, Wayne State University, Detroit, Michigan 48201 [G. H. Y.]

The adenovirus type 5 E1A protein has been demonstrated to elicit antitumor effects through the induction of apoptosis, inhibition of cell cycle progression, induction of differentiated epithelial phenotypes, repression of oncogene expression and function, and sensitization to chemotherapeutic agents and radiation. These unique properties have led to use of the E1A gene in adenoviral and lipid-based gene therapy systems, and it has demonstrated antitumor effects in tumor xenograft model systems. However, the delivery systems used in those studies are best suited for local or intratumoral delivery rather than systemic delivery. Because the effective treatment of many primary tumors as well as metastatic disease requires systemic delivery systems, a novel gene delivery system composed of liposome/protamine/DNA (LPD) was investigated for systemic delivery of the E1A gene. Athymic nude mice bearing human breast (MDA-MB-361) or head and neck (WSUHN-31) tumor xenografts were treated i.v. with LPD-E1A, and the expression of E1A protein and effects on tumor growth were assessed. In the MDA-MB-361 breast model, expression of E1A protein was detected in the tumors after LPD-E1A treatment, which was associated with down-regulation of HER-2/neu protein expression and the presence of apoptotic cells. Tumor volume was also smaller in mice treated with LPD-E1A than in controls in both of the xenograft models. Lastly, LPD-E1A in combination with paclitaxel was more effective than LPD-E1A or paclitaxel alone in the MDA-MB-361 model. Additional preclinical and clinical development of LPD-E1A is warranted for the treatment of advanced or metastatic cancer.

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