Safety studies of the intraperitoneal injection of E1A--liposome complex in mice.
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.
Xing
X
X
Department of Tumor Biology, University of Texas MD Anderson Cancer Center, Houston, USA.
Liu
V
V
Xia
W
W
Stephens
L C
LC
Huang
L
L
Lopez-Berestein
G
G
Hung
M C
MC
D000256:Adenoviridae / Q000235:genetics*; D017500:Adenovirus E1A Proteins / Q000235:genetics*; D000818:Animals; D004279:DNA, Viral / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000502:physiology; D008081:Liposomes; D008099:Liver / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D000090063:Proto-Oncogene Mas; D012449:Safety; D013154:Spleen / Q000276:immunology
D017500:Adenovirus E1A Proteins; D004279:DNA, Viral; D008081:Liposomes; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas