UT Southwestern Researchers Find Way To Control Gene Activity, Opening Way For Cancer Drugs

May 12, 1999

DALLAS - May 12, 1999 - Researchers at UT Southwestern Medical Center at Dallas have developed a method to turn off a gene for telomerase, which activates the continuous division of cancer cells. This finding could aid in the creation of new cancer drugs.

The research team invented a novel method for slipping a small molecule, known as peptide nucleic acid (PNA), into cells, where it then blocked telomerase activity. Telomerase is an enzyme that prevents depletion of the ends -- telomeres -- of chromosomes and allows continuous cell division. The study was reported in the June issue of Chemistry and Biology published today.

Telomeres shorten each time the cell divides, 50 to 70 times during the lifetime of a normal cell. Once the protective tips of DNA are gone, the cells die. All human cells have a gene for telomerase, but it is switched off in normal cells, except embryonic cells, so the enzyme is not manufactured. It is switched on in tumor cells allowing them to divide uncontrollably and be immortal.

The same investigators published a related paper describing the rules for attacking DNA targets with PNAs. That study appeared in March in the Journal of the American Chemical Society.

"A challenge that researchers have faced in trying to switch genes on and off with any efficiency is to identify a small molecule that can enter cells, bind to a target gene and turn the gene off," said Dr. David Corey, co-author of the study, associate professor of pharmacology and biochemistry and a Howard Hughes Medical Institute (HHMI) investigator. "We have a simple way to get PNAs into cells, and we have determined rules guiding their ability to block DNA and RNA targets."

The scientists introduced PNAs into cells by adding a lipid -- a fat-soluble substance. This method allowed delivery of PNAs into the nucleus in almost 100 percent of the tests on two different cell lines, Corey said.

One of the most significant aspects of the work, especially in relation to developing anticancer drugs, is that seven out of 10 of the PNAs tested that targeted different regions of telomerase were able to inhibit the activity of the enzyme. In previous investigations by other scientists trying to use synthetic bits of DNA to block gene activity, only about one in 10 or 20 was similarly successful.

Beyond targeting telomerase, the study's findings also might aid in designing drugs for other diseases and in uncovering the function of the 100,000 genes that make up the human genome.

The Human Genome Project is finding and sequencing all the genes, but now we need to find out what the proteins they produce actually do inside the cells, Corey said. "The efficient way that we have identified to block activity inside cells will allow us to get the multidimensional knowledge necessary to understand cell signaling and regulation.

Now that we know how to get PNAs into cells and the rules governing their binding to DNA and RNA, I can even foresee that these small molecules can make a contribution to development of drugs designed to treat almost any human disease.

Other researchers on the Chemistry and Biology study included: HHMI associate and pharmacology researcher Susan Hamilton; HHMI research technician Carla Simmons; and UT Southwestern Medical Scientist Training Program student Irfan Kathiriya.

The other investigator on the Journal of the American Chemical Society study was Dr. Tsutomu Ishihara, pharmacology postdoctoral fellow and Japanese Society for the Promotion of Science fellow.

Both studies were supported by grants from the National Institutes of Health, the Robert A. Welch Foundation and the Texas Advanced Technology Program.
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