A research team, led by investigators at the Department of Surgery at Jefferson Medical College of Thomas Jefferson University and the Kimmel Cancer Center at Jefferson, has achieved a substantial “kill” of pancreatic cancer cells by using nanoparticles to successfully deliver a deadly diphtheria toxin gene. The findings—to be published in the October issue of Cancer Biology & Therapy—reflect the first time this strategy has been tested in pancreatic cancer cells, and the success seen offers promise for future pre-clinical animal studies, and possibly a new clinical approach, according to the researchers.
The researchers found that delivery of a diphtheria toxin gene inhibited a basic function of pancreatic tumor cells by over 95 percent, resulting in significant cell death of pancreatic cancer cells six days after a single treatment. They also demonstrated that the treatment targets only pancreatic cancer cells and leaves normal cells alone, thus providing a potential therapeutic window. Further, they are targeting a molecule that is found in over three-quarters of pancreatic cancer patients.
This approach was originally developed in ovarian cancer cells by study co-author Janet Sawicki, Ph.D., a member of the Kimmel Cancer Center, and professor at the Lankenau Institute for Medical Research in Wynnewood, Pennsylvania. She and her group had recent success in reducing the size of ovarian tumors following treatment with diphtheria toxin nanoparticles.
The strategy is based on the fact that both ovarian and pancreatic cancer cells significantly over-express a protein found on the cell membrane, called mesothelin. The function of that molecule is unknown, but it is found in the majority of pancreatic tumors and ovarian cancer tumors. Other solid tumors also express mesothelin, but not at such a high rate.
The researchers devised an agent that consists of a bit of mesothelin DNA connected to the gene that produces the toxin from diphtheria, a highly contagious and potentially deadly bacteria, which is now controlled through childhood DPT vaccination. “Naked” DNA is then coated in a polymer to form nanoparticles that are taken up by the cancer cells.
Inside the cells, the nanoparticles biodegrade and the cell machinery senses genetic material from mesothelin. It activates the diphtheria toxin gene, which then turns on production of the toxin which allows the toxin to then do its work on the cancer cells. Within 24 hours of delivery, the toxin disrupted production of protein machinery by over 95 percent, and within six days, a number of cancer cells die or are arrested.
The agent will not attack normal cells because the molecular machinery needed to turn on mesothelin is not found in normal cells.
Release Date: September 23, 2008
Source: Thomas Jefferson University Hospital
Filed Under: Genomics/Proteomics
