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Fox Chase Cancer Center study: Novel DNA-repair gene mutation can cause resistance to cancer drugs

In a paper to be published in the Nov. 25 issue of Proceedings of the National Academy of Sciences, the laboratory of cancer geneticist Alfonso Bellacosa, M.D., of Fox Chase Cancer Center reports new findings linking a novel genetic mutation to the ability of human cancers to resist certain anticancer drugs. The paper, entitled "The Base Excision Repair Enzyme MED1 Mediates DNA Damage Response to Anti-Tumor Drugs and Is Associated with Mismatch Repair System Integrity," will first appear in the PNAS Online Early Edition (www.pnas.org) the week of Nov. 10-14.

Bellacosa's group previously had found the defective gene Med1 to be associated with nonpolyposis colorectal tumors, the most common form of hereditary colorectal cancer (Nature Genetics, November 1999). This gene's protein product, MED1, is an enzyme that normally helps cells repair potentially cancer-causing damage to genes, both directly and indirectly.

"Ironically, the defective MED1 enzyme not only might prevent repairs in normal cells and permit a cancer to start, but in particular, the enzyme also interferes with the effectiveness of some types of chemotherapy," said Bellacosa. The result is a cancer that resists certain widely used drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, a major drug combination used to treat patients with colorectal cancer.

The normal version of the enzyme helps repair DNA damage in two ways. In one repair activity, the enzyme acts like a scissors to remove an altered DNA base in a system called base-excision repair. The enzyme also interacts with another protein in the mismatch-repair system. This system recognizes mismatched DNA bases during a cell's reproductive cycle, when a cell divides and must duplicate its DNA. Ideally, the two strands of DNA's double helix fit together like a zipper. If a duplicated pair of DNA bases forms a mismatch that cannot bond properly, the mismatch-repair system attempts to repair t
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Contact: Karen Carter Mallet
k_carter@fccc.edu
215-728-2700
Fox Chase Cancer Center
10-Nov-2003


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