Safety studies of the intraperitoneal injection of E1A–liposome complex in mice

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 or 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.