Nov. 12, 2003 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 (http://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 the mismatch. If this fails, the system halts the cell's replication cycle and causes the new cell to die--literally, to pop out of its skin in a process called apoptosis.
In addition to helping cells circumvent DNA damage that might otherwise lead to cancer, the mismatch-repair system also plays a critical role in allowing anticancer drugs known as alkylating agents to kill cancer cells. These agents are the oldest and most widely used chemotherapy drugs. They work by damaging the DNA of cancer cells and triggering the mismatch-repair system to interrupt the reproductive cycle and cause apoptosis.
"Our finding that the defective MED1 enzyme produces resistance to these drugs is consistent with previous observations in cell culture models, which show that reduced mismatch-repair proteins cause tolerance or resistance to alkylating agents," Bellacosa explained. "However, it appears that small amounts of DNA damage can be dealt with effectively by reduced levels of these proteins while an effective response to anticancer drugs requires normal amounts."
The experiments by Bellacosa and his colleagues suggest that colorectal tumors with the MED1 deficiency may resist treatment not only with alkylating agents but also with other drugs used against colorectal cancer, such as irinotecan. The research used cell cultures of mouse cell lines, including mice in which the Med1 gene has been inactivated.
"Clinical validation of these hypotheses may have significant implications for treatment selection," Bellacosa and his co-authors conclude. "Additional understanding of the mechanisms of MED1 and mismatch-repair inactivation may suggest methods to overcome drug resistance."
Other study authors include scientific technicians Salvatore Cortellino and Domenico Albino; postdoctoral associates David P. Turner, Ph.D., and René Daniel, M.D., Ph.D.; Anna Marie Skalka, Ph.D., senior vice president for basic science; and medical oncologist Neal J. Meropol, M.D., director of gastrointestinal cancer programs at Fox Chase Cancer Center as well as Christophe Alberti of the Institut Curie in Orsay, France, and former Fox Chase postdoctoral associates Lionel Larue, Ph.D., of the Institut Curie, Filippo Schepis, M.D., of the University of Modena, Italy, and Valeria Masciullo, M.D., of Temple University, Philadelphia.
Fox Chase Cancer Center, one of the nation's first comprehensive cancer centers designated by the National Cancer Institute in 1974, conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at http://www.fccc.edu or call 1-888-FOX CHASE.
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