UT Scientists’ Discovery Can Aid Cancer Treatment

KNOXVILLE – University of Tennessee scientists have made a molecular discovery that can greatly improve the medicines used to treat cancer.

They solved, or made a complete picture, of the structure of a critical molecule called RNR that is involved in forming DNA in the cells of all living organisms and then studied how a specific chemotherapy drug interacts with that molecule.

“When you have the molecular structure of RNR, you can refine drug molecules to make them more potent and more selective,” said UT associate biochemistry professor Chris Dealwis. He is the senior author of two papers appearing in this week’s Proceedings of the National Academy of Sciences about the research. PNAS is one of the world’s most-cited multidisciplinary scientific publications.

Certain drugs used in chemotherapy are designed to attach themselves to the RNR molecule and stop the process that creates new cancer cells. Until now, though, said Dealwis, it was not entirely known the molecular details of how those drugs attached themselves.

The molecule, also known by its full name Ribonucleotide Reductase, maintains the pools of DNA building blocks known as dNTPs that are essential for the cell to replicate. If the RNR molecule in a particular cell malfunctions, it can lead to high mutation rates, causing cancer or cell death.

By creating the first complete description of a large portion of RNR similar to those found in human cells, the UT scientists’ research has already led to a better understanding of how certain cancer drugs work. It also opens the door to a process called structure-based drug design, where drugs are tailored and refined to match to specific sites on molecules, according to Dealwis.

Since the cancer drugs inhibit the process of creating new cancerous cells, they work to effectively stop the spread of cancer.

In their research, Dealwis and his colleagues from UT’s department of Biochemistry & Cellular and Molecular Biology looked specifically at the drug gemcitabine, used in chemotherapy. While it was known that the drug inhibited RNR, the molecular details were not clear.

Their research also led to defining drug interactions at new sites on the RNR molecule that could be exploited for developing a new class of anti-cancer drugs.

The analysis of the structure of RNR was performed using a technique called X-Ray crystallography. By examining X-Rays shone through the crystallized versions of molecules, scientists can define an atomic structure of a molecule. This was the process used in the original studies that revealed the DNA double helix.

The articles appearing in PNAS are entitled, “Structures of Eukaryotic Ribonucleotide Reductase I Define Gemcitabine Diphosphate Binding and Subunit Assembly,” and “Structures of Eukaryotic Ribonucleotide Reductase I Provide Insights into dNTP Regulation.” The other authors on the articles were UT postdoctoral researchers Hai Xu and Catherine Faber, graduate students Tomoaki Uchiki and James Fairman and undergraduate Joseph Racca.

The articles are available online at http://www.pnas.org/cgi/content/abstract/0600443103v1 and http://www.pnas.org/cgi/content/abstract/0600440103v1.

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Contact:

Jay Mayfield, media relations (865-974-9409, jay.mayfield@tennessee.edu)

Chris Dealwis, associate professor of biology, (865-974-4088, cdealwis@utk.edu)