NEW YORK (Reuters Health) - In mice with advanced intra-cranial brain cancer, liposomal-encased antisense gene therapy directed against human epidermal growth factor receptor (EGFR) penetrates the brain and significantly prolongs survival, U.S. scientists report in the June 1st issue of Clinical Cancer Research.
Gene therapy of brain cancer, which “offers the promise of specifically knocking down the expression of oncogenic genes such as EGFR,” is limited by the blood-brain barrier, Dr. William Pardridge of the University of California in Los Angeles and colleagues note in their report.
His group has developed and validated in an animal model a gene therapy delivery system that crosses the blood-brain barrier. It uses pegylated immunoliposomes (PILs) to deliver a genetically engineered non-viral plasmid directly to cancer cells in the brain. The plasmid encodes a short hairpin RNA (shRNA) to silence expression of EGFR, a technology known as RNA interference (RNAi).
In cultured glioma cells, the delivery of this PIL-encased RNAi expression plasmid suppressed EGFR function by 95%. In adult mice with advanced intra-cranial brain cancer, weekly IV administration reduced tumor expression of EGFR and upped survival time by 88% compared with untreated controls.
“By solving the delivery problem, powerful molecular tools and therapies such as RNAi can be moved to clinical trials,” Dr. Pardridge said in a statement.
The next step, he told Reuters Health, is to use this approach to simultaneously take out tumorigenic genes and to replace mutated tumor suppressor genes. “Just as in chemotherapy for cancer using 3-4-5 drugs, gene therapy for cancer needs to be polygenic,” he explained.
“In other words, you get cancer because of four or five mutations in the same cell. You need to knockout the EGFR [and] the RAS oncogene and you need to knock in a mutated p53 [and] a mutated p10. When you come at cancer at these four different approaches, you’re going to bring the cancer cell to its knees so that the endogenous immune system can kill it,” Dr. Pardridge said.
Source: Clin Cancer Res 2004. [ Google search on this article ]
MeSH Headings:Animal Diseases: Biological Therapy: Disease Models, Animal: Drug Therapy: Genetic Engineering: Genetic Techniques: Membrane Proteins: Investigative Techniques: Receptors, Cell Surface: Receptor, Epidermal Growth Factor: Receptors, Gastrointestinal Hormone: Therapeutics: Gene Therapy: Drug Delivery Systems: Receptors, Growth Factor: Receptors, Peptide: Analytical, Diagnostic and Therapeutic Techniques and Equipment: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
