Disabling Enzyme That Causes RUNAWAY GROWTH - cancer - Brief Article

In a nightmare version of eternal life, cancer cells continue to divide, reproducing themselves endlessly until the patient dies. The growth of tumors is aided by an enzyme called telomerase, which repairs the ends of chromosomes in cancer cells in a way not possible with most normal tissue. Researchers seeking less painful, more effective cancer treatments are focusing on ways to block the action of the enzyme by manipulating the structure of chromosomes in cancer cells. Telomerase is not present in most normal cells, but is associated with the uncontrolled growth of 80-90% of all tumor cells.

Scientists at The University of Texas at Austin have discovered that substances they hope to use as anti-cancer medicines can accelerate the formation of naturally occurring structures that appear to disable the rogue enzyme. According to Laurence Hurley, professor of medicinal chemistry, box-like structures, referred to as G-quadruplexes, are thought to develop at the ends of chromosomes during the life cycles of cancer cells and are considered promising targets for anti-cancer agents.

Chemotherapy works like a shotgun, killing both cancer and normal cells. Scientists are looking for an agent that will target just cancer cells. The good news is that the small molecular-weight compounds produced in the lab appear to target telomerase by interfering with a structure found at the ends of chromosomes. They also concentrate themselves in tumors and not in healthy areas of the body. Thus, they would act only against the cancer cells.

"The compounds are much less toxic. They show only slight toxicity in comparison to most chemotherapy drugs," Hurley explains. "The significance of our most recent discovery is that the compounds we are working with appear to trap abnormal, intertwined chromosomal structures in cancer cells and slow the growth of tumors." The existence of G-quadruplex DNA in humans has not been proved definitively, but Hurley says there is "an overwhelming body of circumstantial evidence" that the structures do exist, sufficient evidence for scientists to pursue this avenue of research.

Chromosomes consist of long strings of molecules containing genetic information needed for cells to divide and replicate themselves over and over again. The ends of chromosomes are capped like shoelaces with structures called telomeres.

In normal cells, bits of information at each end of the chromosomal "shoelace" tend to get lost each time a cell divides, naturally limiting the lifetime of a cell. In cancer cells, there is a mechanism for adding back the lost end of the chromosomes, with telomerase playing an integral role in renewing the ends every time. That is one of the reasons why cancer cells continue to reproduce and grow out of control. In contrast, normal cells wear out and die.

The structures at the end of the strands scientists are trying to manipulate are extremely complex and change shape depending on the point in the life cycle of the cell. At a certain point in the cycle, the end of a chromosome can, theoretically, change from a single strand into a four-stranded structure. This is G-quadruplex DNA, or G4 DNA. When this structure folds over on itself, as may naturally occur in the cycle, the action of telomerase is stopped.

The fact that the University of Texas researchers have been able to accelerate the formation and folding of G4 DNA is a major step forward because it means they can manipulate the process. "What we didn't know before is that we can start with a single strand of DNA, add the compound, and make it fold over," Hurley points out. While other enzymes normally would act to unfold the DNA structure again, the compounds both "accelerate the folding and prevent the enzymes that would unfold it again from acting."

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