U. RESEARCHERS USE POLYMERS TO FURTHER CANCER RESEARCH
Researchers at the University of Utah are using polymers, or large chains of molecules, in an effort to make anticancer drugs more effective. And they have recently shown these polymer creations to be a powerful weapon in combating cancer's resistance to subsequent chemotherapy treatments.
Their findings are expected to lead to the design of better drug-delivery systems in the fight against cancer.
Jindrich (Henry) Kopecek, chairman of the Department of Pharmaceutics and Pharmaceutical Chemistry, leads a large group of researchers in a project that links water-soluble polymers with anti-cancer drugs in a molecular marriage called a bioconjugate.
The researchers chose the polymers because, when linked with anti- cancer drugs, these bioconjugates change the way in which the drugs enter the cancer cells.
"The idea is to get the drug where its action is needed," Kopecek says, "and to keep it there."
Used alone, the relatively small molecules of anticancer drugs usually enter the cancer cells by the process of diffusion; that is, they gradually seep through the cell membrane. While such a delivery process may have some effectiveness the first time cancer cells are attacked through chemotherapy, on subsequent treatments the cells often develop a resistance -- not only to that drug, but to other anticancer agents as well.
This multidrug resistance has been a long problem in the treatment of cancer. But using polymer bioconjugates, Kopecek, research associate Tamara Minko and research professor Pavla Kopeckova have found a way to overcome this resistance.
When anticancer drugs are attached to polymers, the resulting large molecules are too large to enter a cell by diffusion. Rather, they're introduced into the cell by a process called endocytosis. The cell membrane engulfs the molecule and forms a sac around it, pulling it deep within the cell.
With this process, the drug is eventually released closer to the nucleus of the cell, lessening the chances that a drug-resistant cancer cell will quickly expel it before it has a chance to work. More of the drug remains in the cancer cell for a longer period.
"We have shown that binding drugs to polymers not only changes the mechanism of cell entry, but also the way genes are activated and the way cells commit 'suicide,' called apoptosis," Kopecek said. "Many questions remain to be answered, but it is clear that this approach opens a rational way for the design of new, more efficient anticancer drug-delivery systems."
Binding anticancer drugs to polymers has another advantage, Kopecek says. There is a decrease in non-specific toxicity, meaning less of the chemotherapy poison affects normal cells. Bound to the polymer, the anticancer drugs don't enter the heart -- or other healthy tissue -- quite as readily.
One other potential advantage of using these bioconjugates, says Kopecek, is the possibility of attaching part or all of an antibody to the polymer- drug combination. Antibodies could be chosen for their attraction to a certain type of cells, ensuring that a higher amount of the drug gets delivered right to the tumor cells that need it.
Several bioconjugates are now in clinical trials.
Kopecek said while it is important to develop new cancer drugs, it's equally imperative that researchers design newer, more effective ways of delivering those drugs to the right cells. Paraphrasing a Harvard researcher, Kopecek said creating drugs without also creating better drug-delivery systems is like developing all sorts of fantastic new automobiles, only to neglect the roads and bridges they ride upon.
"We are working on the roads and bridges," Kopecek said.
Contact: Henry Kopecek, 801 581-7831 ([email protected])
Writer: Mark Saal, 801 581-7932 ([email protected])
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