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The war on cancer has been long and frustrating. Even with a steady stream of new drugs and improvements in delivering them to malignant cells, dramatic results have been slow in coming. This group of deadly diseases continues to be a major killer. But scientists at Washington University in St. Louis may be on the verge of adding a potent new weapon to the doctor's arsenal. Although the research is still in the very early stages, scientists have discovered a way to use unique genetic sequences from a patient's own diseased cells to bring together two components that combine to create a drug that only works inside infected cells.
The technique is so sensitive that it can distinguish between a healthy and diseased cell even if only one DNA building block is different, leaving normal cells untouched. It also has promise in treating viral diseases, possibly even AIDS. "We are making direct use of genetic information to signal a particular cell for destruction," says John-Stephen Taylor, a professor of chemistry, who headed the research effort.
Taylor and his colleague Zhaochun Ma, who reported on the development Aug. 20 at the annual meeting of the American Chemical Society in Washington, use synthetic genetic sequences that act like a trigger to release the drug. Rapid advances in reading cells' genetic code and the ability to create synthetic analogs have made it possible to prepare a custom-tailored drug in a matter of hours, says Taylor.
HOW IT WORKS. First, the researchers' obtain diseased cells and identify genetic sequences that make them unique from healthy ones. Then they prepare a synthetic mirror image of half the sequence that will bind to the whole sequence in the cell like a lock and a key. To that, they attach a "pro-drug" -- a poison that will be released only if it's exposed to a catalyst. They attach a catalyst to the other half of the synthetic sequence and, when the two compounds are injected into a patient, they move freely in and out of all the cells in the body. But only in those cells that are diseased will they attach side-by-side to their targets. When that happens, the catalyst triggers the reaction that produces a deadly toxin.
Since the drug is literally manufactured inside the cell, the infected cell is destroyed while others are untouched. In contrast, many chemotherapy drugs now in use are poisonous to all cells -- but slightly more so to cancerous ones. Of course, targeting specific cells for destruction and leaving others unharmed is the ultimate goal of most drugmakers. But by taking advantage of a patient's own genetics, Taylor's technique has the promise of being the most specific yet. "I hope this will become the best way to cure cancer and viral diseases, as well as other infectious diseases, such as antibiotic-resistant bacteria, fungi, and parasites," says Taylor.
Much work remains before that day arrives, however. So far, the Washington University researchers have tested the technique only on cells in cultures. Their early research will be published soon in the Proceedings of the National Academy of Sciences. Now, they're planning additional experiments to find the best combination of drug and catalyst before beginning tests on laboratory animals. Human trials may be several years away.
Many such ideas have failed to pass the muster of rigorous testing in the past. But if this one succeeds, it presages a new era in medicine. Today, physicians select drugs from a list of those likely to work -- and wait for the results. And they scour the jungles of the world for new, potent compounds. If this effort bears out, drugs instead will be concocted to act directly on each patient's infected cells, linked intimately to the genetics and chemistry of the patient and the infection.
Copyright 2000, by The McGraw-Hill Companies Inc. All rights reserved.
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