Aug. 22, 2000 Imagine a day when a cancer patient can have a blood or biopsy sample fed into a DNA diagnostics machine that takes the disease-state DNA results and within hours comes up with a tailored drug/catalyst therapy. This treatment will kill the cancerous cells in the body and leave the others unharmed, and it is capable of beating the cancer even as it mutates.
John-Stephen Taylor, Ph.D., professor of chemistry in Arts and Sciences at Washington University in St. Louis, and his research team have taken the first step to make this happen by designing a new approach to chemotherapy that makes direct use of genetic material as a trigger to annihilate cancer or virally infected cells.
This innovative approach would facilitate the selective destruction of harmful cancer or viral cells, which has always been the less-than-realized basis for chemotherapy.
"All throughout history, the development of drugs has been based on trying to find a molecule toxic only to the pathogen or organism you want to kill," Taylor says.
But he notes that recent advancements in mapping the human genome and developing DNA chips have provided opportunities to determine the exact genetic composition of specific diseases such as cancer.
"Once you know the sequence of a nucleic acid such as DNA or RNA, it's very easy to make a molecule that binds specifically to that sequence by making use of Watson/Crick base-paring rules," he explains. "So the beauty of nucleic acids is that they present a trivial way of targeting any specific sequence you want."
Current experimental approaches that take advantage of the ease by which specific nucleic acid sequences can be targeted by Watson/Crick rules, such as anti-sense and anti-gene approaches, are based on binding to and then attacking the disease-specific nucleic acid sequences in an attempt to inactivate cancerous cells by interfering with their genetic codes. But it's difficult to predict the outcome of attacking a particular disease-specific nucleic acid sequence. Also, when attacking the genetic material directly, undesirable collateral damage can arise because sequences other than those targeted may be damaged.
Taylor and his group have developed an entirely different approach to disease-specific chemotherapeutic agents that makes use of Watson/Crick base-pairing rules. They came up with a nucleic acid-triggered catalytic drug release system that they've shown works in an in vitro model system. Instead of using the disease-specific nucleic acid as a target, it is used as a trigger to cause the release of a cytotoxic agent. The basic idea is to use a disease-specific nucleic acid sequence to bring together a prodrug component and a catalytic component capable of releasing the drug from the prodrug. A prodrug is an inactive form of a drug that has no therapeutic value until it is converted into the active form of a drug.
To make the prodrug component, Zaochun Ma, Ph.D., Taylor's post-doctoral researcher at Washington University, attached a drug to a synthetic DNA sequence that is specifically designed to recognize one half of a DNA sequence representing the disease-specific nucleic acid sequence. To make the catalytic component, a catalyst that has the ability to release the drug from the prodrug component is attached to synthetic DNA that recognizes the other half of the DNA sequence. When the catalytic and prodrug components are mixed in the presence of the DNA sequence, the drug is released from the prodrug component.
"Basically, we are using the nucleic acid unique to the cancerous DNA as a template to bring together the prodrug and the catalyst,' Taylor explains. "Instead of using the nucleic acid as a target for the action of a drug, we use nucleic acid as a trigger. It's better to use genetic information as a trigger than as a target."
Ma described the method in a paper delivered at the annual meeting of the American Chemical Society, Aug. 20, 2000, in Washington, D.C. The paper will be published later this year in the Proceedings of the National Academy of Sciences.
By combining the catalytic component and the complementary DNA sequence, Taylor has created a synthetic enzyme out of viral or cancerous DNA that can cause the release of the drug in the diseased cell.
"Only in the presence of the specific sequence unique to the cancer or virus can these two, prodrug and catalyst, be brought together so that the catalyst can snip off the drug," he explains. Without the specific sequence of the cancer or viral cell, neither the drug nor the catalyst can get together. Thus, healthy cells are unharmed.
Taylor says it may take many years to develop a therapy based on his method, but he is optimistic that the method provides another direction, one that could rapidly respond to viral diseases or cancer as fast as they mutate. He says the catalyst/prodrug/DNA trigger system could expand beyond the horizons of anti-viral and anti-cancer therapy to other diseases.
"The beauty of the system is that you could use it for any infectious disease or cancer," Taylor says. "You don't have to go out and search the plant world for new drugs. With this system you can create drugs based on straightforward Watson/Crick base pairing."
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