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Safety studies of the intraperitoneal injection of E1A--liposome complex in mice
1Department of Tumor Biology, University of Texas MD Anderson Cancer Center, Houston, USA.
Abstract:
The HER-2/neu (also called c-erbB-2) proto-oncogene is overexpressed in many human cancer cells, including those of breast cancer and ovarian cancer. We have previously shown that adenovirus 5 E1A inhibits HER-2/neu transcription and functions as a tumor suppressor gene in HER-2/neu-overexpressing cancer cells. Liposome-mediated E1A gene transfer suppresses tumor development and prolongs survival of tumor-bearing mice. In support of a phase I clinical trial of an E1A-liposome complex administered to patients with HER-2/neu-overexpressing breast of ovarian cancer, we conducted a series of studies to evaluate the safety of intraperitoneal injection of E1A in normal mice. The cumulative doses used were from five to 40 times the DNA-lipid starting dose proposed for the phase I clinical trial. In this dosing range, the administration of the E1A-liposome complex had no adverse effects on renal, hepatic and hematological parameters studied. No major organ pathologic changes were observed. We concluded that intraperitoneal administration of E1A-liposome complex at the proposed dose would not be expected to produce significant toxicity. The E1A-liposome clinical trial was recently approved by the Recombinant DNA Advisory Committee and Food and Drug Administration for a phase I trial in patients with HER-2/neu-overexpressing breast and ovarian cancer.
Insights
Adenovirus E1A gene therapy shows promise for HER-2/neu-overexpressing cancers. Intraperitoneal E1A-liposome complex administration demonstrated safety in mice, supporting upcoming human clinical trials.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- HER-2/neu proto-oncogene overexpression is common in breast and ovarian cancers.
- Adenovirus 5 E1A inhibits HER-2/neu transcription and acts as a tumor suppressor.
- Previous studies demonstrated E1A gene transfer suppresses tumors and prolongs survival in mice.
Purpose of the Study:
- Evaluate the safety of intraperitoneal E1A-liposome complex administration in normal mice.
- Support a Phase I clinical trial for patients with HER-2/neu-overexpressing breast and ovarian cancer.
Main Methods:
- Administration of E1A-liposome complex via intraperitoneal injection in mice.
- Doses ranged from five to 40 times the proposed clinical trial starting dose.
- Assessment of renal, hepatic, and hematological parameters, along with pathological examination of major organs.
Main Results:
- No adverse effects observed on renal, hepatic, or hematological parameters within the tested dose range.
- No significant pathological changes were detected in major organs.
- The E1A-liposome complex was found to be safe at doses significantly exceeding the proposed clinical starting dose.
Conclusions:
- Intraperitoneal administration of E1A-liposome complex is unlikely to cause significant toxicity at the proposed clinical dose.
- The findings support the initiation of a Phase I clinical trial for E1A-liposome complex in patients with HER-2/neu-overexpressing cancers.
- This study provides a crucial safety evaluation for a novel gene therapy approach in oncology.