University of Mississippi Medical Center의 한 생화학자는 대부분의 항암제 종류에 대해서 내성을 갖고 있는 암세포들을 파괴하며, 그것이 결합되어 있는 DNA 구조를 변화시킬 수 있는 새로운 분자를 발견해낸 연구팀의 멤버이다. 이러한 연구결과들은 2001년 5월에 발표된 Bioorganic & Medicinal Chemistry지에 게재되었다.
'Octamer' Intercalator Distorts DNA Structure
A biochemist at the University of Mississippi Medical Center is part of a team that has developed a new molecule that kills cancer cells resistant to most anti-cancer drugs and also changes the structure of DNA to which it is bound. The results are published in the May 2001 issue of Bioorganic & Medicinal Chemistry
To some, the significance of this discovery is the possibility of a new drug that will fight cancer current drugs can't touch.
But author Brad Chaires cautions, "That's way off. From this point, it could be 10 years before a drug based on this work is available to cancer patients. I'm a basic scientist having fun in the lab, thinking up ways to change existing molecules to make new ones."
To scientists, however, the work holds "classic significance." To those scientists around the world who daily delve into the mysteries of DNA, this research represents the first clear indication that small molecules can change the structure of DNA. Small molecules could change the structure of proteins, but not DNA, it was thought. Chaires, who likens his work to molecular engineering, designs molecules that his colleague at the MD Anderson Cancer Center makes. His chief collaborator is Dr. Waldemar Priebe, a professor of medicinal chemistry. Dr. John O. Trent is their partner at the University of Louisville. Trent is a computational chemist who uses sophisticated computer programs to make realistic structural models of drug-DNA complexes.
The most recently developed compound is a variation on daunorubicin, one of the most common drugs in the current arsenal against cancer.
"It's actually a mirror image of daunorubicin," Chaires says of the new molecule, WP900. The nomenclature contains the initials of the designer, and the sequence of its development. WP900 is the nine hundredth molecule synthesized by Waldemar Priebe.
The original daunorubicin is a natural product produced by a microorganism found in the soil. The original molecule?in the analogy of the mirror image?is only one side of the mirror. "It (the original) likes right-handed DNA," Chaires explains. "Right handed" DNA is the part of the double helix that spirals toward the right. Most DNA is "right handed," but a small portion spirals toward the left.
The new molecule, WP900, selects the left-handed DNA, and in so doing, changes the very structure of DNA to spiral left. This, Chaires said, may be how the new molecule kills cancer cells, and especially those cancer cells that are resistant to other cancer fighting drugs.
Chaires and his colleagues hold a patent, issued in 1999, on earlier work with daunorubicin. In that work, they (as suggested by Chaires and carried out by Priebe) linked two daunorubicin molecules so that the drug's ability to bind with the DNA of cancer cells was enhanced. In fact, Chaires said the new molecule, bis-daunorubicin, bound to DNA a "million times tighter" than the original molecule.
If a cancer drug is developed from this molecule, it could mean that the worst part of cancer treatment can be avoided. A drug that can infiltrate the DNA of cancer cells so thoroughly can be given in much smaller doses than the current duanorubicin, thereby greatly minimizing the side effects of current chemotherapy.
This compound, WP631, showed its potential in killing melanoma cells in cultures at the National Cancer Institute. Melanoma is an often life-threatening cancer that appears on the skin and spreads rapidly to other parts of the body.
Chaires has been studying daunorubicin and its anthracycline cousins, doxurubicin and adriamycin, for the past 20-30 years. "I looked around for compounds to study that were in clinical use but were, for the most part, mysteries in terms of their actions."
It's all part of what Chaires calls "rational drug design." "You look at current drugs, see how they work, and see if you can use that as a model for developing new drugs."
(소스: http://www.bio.com/)
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