12 March 2012

New Development In Chemotherapy Reduces Side Effects

In a study published in Nature online, scientists are led to a discovery that could reduce the side effects of chemotherapy.

Chemotherapy or "chemo", is the use of medicines or drugs to treat disease. This procedure is almost always associated with cancer. It works throughout the whole body unlike surgical or and radiation therapy where a certain part of the body is targeted to remove, kill, or damage cancer cells present there. Chemo can kill cancer cells that have metastasized or spread to parts of the body far away from the primary (original) tumor.

More than 100 chemo drugs are used in many combinations. A single chemo drug can be used to treat cancer. But for the most part, the drugs work better when used in certain combinations. This is called combination chemotherapy. A combination of drugs with different actions can work together to kill more cancer cells. It can also reduce the chance that the cancer may become resistant to any one chemo drug.

A team of researchers at Duke University has determined the structure of a key molecule that can carry chemotherapy and anti-viral drugs into cells, which could help to create more effective drugs with fewer effects to healthy tissue.

"Knowing the structure and properties of the transporter molecule may be the key to changing the way that some chemotherapies, for example, could work in the body to prevent tumor growth," said senior author Seok-Yong Lee, Ph.D., assistant professor of biochemistry at Duke.

Video: Understanding Chemotherapy

The transporter molecule, called a concentrative nucleoside transporter, works by moving nucleosides, the building blocks of DNA and RNA, from the outside to the inside of cells. It also transports nucleoside-like chemo drugs through cell membranes. Once inside the cells, the nucleoside-like drugs are modified into nucleotides that are incorporated into DNA in ways that prevent tumor cells from dividing and functioning.

"We discovered the structure of the transporter molecule, and now we believe it is possible to improve nucleoside drugs to be better recognized by a particular form of the transporter molecule that resides in certain types of tissue," Lee said. "Now we know the transporter molecule has three forms, which recognize different drugs and reside in different tissues."

The team determined the chemical and physical principles a transporter molecule uses to recognize the nucleosides, "so if you can improve the interactions between the transporter and the drug, you won't need as much of the drug to get it into the tumor cells efficiently," Lee said. "Knowing the shape of the transporters will let scientists design drugs that are recognized well by this transporter."

Because the drugs enter healthy cells as well as tumor cells, giving a lower dose of drug that targets tumor tissue would be the best scenario, said Lee, who is also a member of the Duke Ion Channel Research Unit. "Healthy cells don't divide as often as tumor cells, so lowering the amount of drug given overall would be an effective approach to killing tumors while protecting patients."

The researchers studied transporter molecules from Vibrio cholera, a comma-shaped bacterium. The bacterial transporter serves as a good model system for studying human transporters because they share similar amino acid sequences. They found that both the human and bacterial transporter use a sodium gradient to import nucleosides and drugs into the cells.

The next step will be to try to understand which features of the transporter confer the ability to recognize certain chemo drugs and ultimately to design drugs that can easily enter the cells.

This work won a prize for Dr. Lee, the National Institute of General Medical Sciences Award, which he will receive at the Biophysical Society meeting in February.


Duke University Medical Center
Duke Ion Channel Research Unit
Understanding Chemotherapy: A Guide for Patients and Families
National Institute of General Medical Sciences
Biophysical Society
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