Lack of toxicity of EGFR antisense gene therapy.

Abstract

PURPOSE:

EGFR is overexpressed in many human cancer cells, including head and neck squamous cell carcinoma (HNSCC). We have previously shown that elevated EGFR levels in the primary HNSCC tumor are associated with decreased survival. Reduction of EGFR tumor expression levels using an antisense EGFR sequence under the control of the U6 small nuclear RNA promoter abrogates tumor growth in a head and neck xenograft model. In support of a phase I clinical trial of an EGFR antisense gene-liposome complex administered to HNSCC patients, we conducted a series of studies to evaluate the safety of intralesional injections of EGFR liposomal antisense gene therapy in normal mice.

METHODS:

Three dose tiers were examined including the starting DNA-lipid dose for the clinical trial.

RESULTS:

Tissues and blood were harvested from mice treated with the liposome-mediated gene therapy and control mice at several time points for analysis. In this dosing range, administration of the antisense EGFR DNA-liposome complex had no apparent adverse effect on renal, hepatic and hematologic parameters studied. No major organ pathologic changes were observed.

CONCLUSIONS:

These results suggest that the toxicity of intralesional EGFR antisense DNA plus liposomes is restricted to a self-limited inflammation at the injection site, and may be well-tolerated in the clinical setting. EGFR antisense gene therapy was reviewed by the Recombinant DNA Advisory Committee and the Food and Drug Administration, and a phase I clinical trial is currently underway in patients with advanced HNSCC.

• Authors: Qing Zeng, Peter M Kanter, Rajiv Dhir, William E Gooding, Leaf Huang, Jennifer Rubin Grandis
• Journal: Journal of experimental therapeutics & oncology (J Exp Ther Oncol) 2002 May-Jun Vol. 2 Issue 3 Pg. 174-86 ISSN: 1359-4117 [Print] United States
• PMID: 12415634 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Antisense
• Liposomes
• ErbB Receptors

Topics

• Animals
• Bone Marrow (drug effects)
• DNA, Antisense (administration & dosage, adverse effects)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Female
• Genetic Therapy (methods)
• Hyperplasia
• Injections, Intramuscular
• Kidney (drug effects, physiology)
• Liposomes
• Liver (drug effects, physiology)
• Lymph Nodes (drug effects, pathology)
• Male
• Mice
• Mice, Inbred ICR