Duke Researchers Link Brain Tumor Drug Resistance To Mismatch Repair Deficiency

July 15, 1997

DURHAM, N.C. -- The failure of chemotherapy to stop glioblastoma, an aggressive brain tumor, may be linked to a deficiency in a naturally occurring "fix-it" material in the cell, according to Duke University Medical Center researchers.

In a study reported in the July 15 issue of Cancer Research, Duke cancer and biochemistry specialists found that glioblastoma multiforme (GBM) tumors that had become resistant to chemotherapeutic agents showed defects in the cellular mismatch repair system, a key factor in quelling cancer cells. The findings reinforce researchers' beliefs that mismatch repair has broad impact on human tumor cell production.

"This study extends results that have been observed in tissue culture cells to human tumors in animals," said Paul Modrich, Ph.D., a Howard Hughes investigator in biochemistry at Duke and lead author of the study. "It renders it likely that this drug resistance is also a significant effect in cancer patients."

Dr. Henry Friedman, chief of pediatric neuro-oncology at Duke and primary investigator of the study funded by the National Institutes of Health, said the research may quickly lead to more effective treatment of GBM, one of the most common and virulent brain tumors.

"The major problem in the treatment of cancer is drug resistance," Friedman said. "Tumor cells become resistant, or could be resistant at diagnosis. The cells escape the effects of the drug, repopulate, and the patient ultimately succumbs to the tumor. If we can determine the mechanisms of resistance to a drug, then we can opt for different therapy or, eventually, alter that mechanism of resistance."

While growing human GBM tumors on mouse models, the researchers treated the tumors with procarbazine, a drug commonly prescribed alone or in combination with other drugs in therapy for the brain cancer. Though procarbazine is a frontline drug treatment, most patients ultimately develop resistance to it and it ceases to check tumor growth. The tumors growing on mice developed resistance to the drug after nine serial treatments, giving the researchers a way to study the resistance mechanism.

Procarbazine is a methylator, an agent that poisons cancer cells by attaching a chemical compound called a methyl group to DNA. In the normal sequence of cell replication, the attached compounds alert the mismatch repair mechanism in the cell that a mutation has occurred, according to Friedman. That triggers a "toxic event," and ultimate destruction of the tumor cell.

"All cells go through changes, or mutations, day to day. It's normal in cell reproduction, and it's the job of mismatch repair material -- which is a family of proteins -- to correct some of the disorder that occurs in cell replication," Friedman said. "What we found was that the resistant tumor cells had a mutation in mismatch repair that was not present in the 'parent' tumor -- the tumor graft that didn't seem to be resistant to drugs at first. We think the resulting deficiency led to the resistance to procarbazine and other methylators."

"Mismatch repair's function is mutation avoidance; it corrects errors and prevents mutations, but it also targets certain DNA-damaging cells to die if exposed to certain agents," Modrich said. "When mismatch repair is inactivated, you predispose cells to a high mutation rate."

This summer, Friedman and Modrich will begin studying the mismatch repair activity in patients' biopsied malignant GBM. If the findings from the xenograft, or animal-grown, tumors bear out, clinical application could begin in trials in the next year, Friedman said.

"It may soon be possible to analyze the patient's tumor at biopsy to determine the likelihood of resistance to the methylators, and to tailor treatment accordingly to reduce tumor progression, and that means faster, more effective treatment," Friedman said.

Other researchers on the project are Stewart Johnson, Qing Dong, Clifford Schold, Ahmed Rasheed, Dr. Sandra Bigner, Francis Ail-Osman, Eileen Dolan, Dr. Michael Colvin, Peter Houghton, Glen Germain, James Drummond, Stephen Keir, Susan Marcelli and Dr. Darell Bigner.

Duke University

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