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Systemic gene therapy in human xenograft tumor models by liposomal delivery of the E1A gene
Naoto T Ueno1, Chandra Bartholomeusz, Weiya Xia
1Breast Cancer Research Program Core Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
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.
Insights
A novel liposome/protamine/DNA (LPD) system effectively delivered the adenovirus type 5 E1A gene systemically, showing antitumor effects in preclinical models. This LPD-E1A approach warrants further development for treating advanced cancers.
Area of Science:
- Oncology
- Gene Therapy
- Nanotechnology
Background:
- Adenovirus type 5 E1A protein exhibits potent antitumor properties, including apoptosis induction and cell cycle inhibition.
- Previous gene therapy approaches using E1A were limited by local delivery systems, hindering treatment of metastatic cancers.
Purpose of the Study:
- To investigate a novel liposome/protamine/DNA (LPD) gene delivery system for systemic E1A gene delivery.
- To evaluate the antitumor efficacy of systemically delivered E1A using the LPD system in preclinical cancer models.
Main Methods:
- Developed a liposome/protamine/DNA (LPD) formulation for E1A gene delivery (LPD-E1A).
- Administered LPD-E1A intravenously to athymic nude mice bearing human breast (MDA-MB-361) or head and neck (WSUHN-31) tumor xenografts.
- Assessed E1A protein expression, HER-2/neu downregulation, apoptosis, tumor growth inhibition, and combination therapy effects with paclitaxel.
Main Results:
- Systemic LPD-E1A treatment led to detectable E1A protein expression in tumors.
- Observed HER-2/neu protein downregulation and increased apoptosis in MDA-MB-361 tumors post-treatment.
- Reduced tumor volume in both xenograft models compared to controls.
- LPD-E1A combined with paclitaxel demonstrated enhanced efficacy in the breast cancer model.
Conclusions:
- The LPD system enables effective systemic delivery of the E1A gene for cancer therapy.
- LPD-E1A shows significant preclinical antitumor activity and sensitizes tumors to chemotherapy.
- Further preclinical and clinical development of LPD-E1A is recommended for advanced and metastatic cancers.