Combination gene therapy delivered in lipid-based nanoparticles drastically reduces the number and size of human non-small cell lung cancer tumors in mice.
The study, by researchers at The University of Texas M. D. Anderson Cancer Center and the University of Texas Southwestern Medical Center is published in Cancer Research.

Two tumor-suppressing genes given intravenously reduced cancer separately but had their most powerful effect when administered together, cutting the number of tumors per mouse by 75 percent and the weight of tumors by 80 percent.

The genes wrapped in the nanoparticles were p53, a well-known tumor suppressor that works by causing defective cells to commit suicide and is often shut down or defective in cancer cells, and FUS1, a tumor-suppressor discovered by the research group that is deficient in most human lung cancers. Each nanoparticle carried one of the two genes.

The Cancer Research paper reports that FUS1 works with p53 to force the lung cancer cells to kill themselves - a process known as apoptosis.

Further analysis showed that the combination achieved greater cell suicide because FUS1 suppresses a gene that expresses a protein known to rapidly degrade p53, says senior author Lin Ji, at M. D. Anderson.

The FUS1/p53 combination also activates a cell suicide pathway based in the cells' mitochondria, their energy powerhouse.

Lab experiments first showed that the gene combination cut the number of viable cells in four lines of human non-small cell lung cancer by 70 to 80 percent 48 hours after treatment while leaving a control group of normal cells unaffected. The cancer cell lines treated with the gene combination had 2 to 3 times more cells killed by apoptosis than either gene nanoparticle had individually. The research team then confirmed these findings in the mouse studies.

The nanoparticle delivery system, which the researchers have used for years, consists of a plasmid gene expression cassette loaded with DNA that encodes either the p53 or the FUS1 protein. This is wrapped tightly in a form of cholesterol to protect it from the body's defense mechanisms. "You can't deliver naked DNA for cancer therapy," Ji says.

The nanoparticles accumulate mainly in the lungs, particularly in the tumors, Ji says. The positively charged nanoparticles are delivered to the negatively charged cancer cell membrane and taken into the cell, where the genes repeatedly express either p53 or FUS1 tumor-suppressing proteins.

Source: University of Texas M. D. Anderson Cancer Center, 2007

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