Knotty DNA offers cancer-drug target

DNA molecules normally exist as paired strands arranged in a spiral staircase, but sometimes they form knotty clumps called quadruplexes. This happens most often along stretches of DNA with repetitive sequences of the molecule’s nucleotide bases.

At least in test-tube experiments, such quadruplexes are unusually common in regions of DNA that host genes implicated in cancer. The formation of quadruplexes, scientists speculate, could lead to activation of cancer-promoting genes.

In cell cultures, these knotty structures also form in telomeres, which are the small caps at the end of chromosomes. Telomeres normally shorten each time a cell divides, but many cancer cells produce an enzyme called telomerase that artificially extends telomeres. Longer telomeres enable cells to divide more often.

Quadruplexes apparently attract telomerase, says Laurence H. Hurley of the University of Arizona Health Sciences Center in Tucson. He points out that quadruplexes have so far only been observed in test tubes, although many cells contain enzymes that would facilitate the folding of DNA into quadruplexes.

Hurley and his colleagues have developed agents that promote the formation of quadruplexes, bind to them, and prevent them from reverting into the more familiar ladderlike structure.

One such agent, called TMPyP4, reduces the activation of a cancer-causing gene called myc-1, which is found in about 80 percent of all cancers, Hurley reports. That activity may explain why TMPyP4 also reduces production of telomerase, he says. “We’ve demonstrated that, in cell culture, these compounds can result in telomere shortening and cell death,” he says.

Additionally, mice injected with breast or brain cancer cells live longer when given agents that bind to quadruplexes, he reports. This is indirect evidence that these knotty structures exist in live animals, says Hurley.

“Quadruplexes represent a really exciting direction for DNA targets,” says Edward Sausville of the National Cancer Institute in Rockville, Md. “Quadruplex structures are unique to the economy of cancer cells,” he says, so agents that bind to quadruplexes may become especially valuable as new treatments.