Brain Tumor Drug Resistance Linked to Mismatch Repair Deficiency

September 1, 1997

The failure of chemotherapy to stop glioblastoma may be linked to a deficiency in DNA repair capability in the cell, according

The failure of chemotherapy to stop glioblastoma may be linked to adeficiency in DNA repair capability in the cell, according to Duke UniversityMedical Center researchers.

In a study reported in Cancer Research, Duke cancer and biochemistryspecialists found that glioblastoma multiforme (GBM) tumors that had becomeresistant to chemotherapeutic agents showed defects in the cellular mismatchrepair system, a key factor in quelling cancer cells. The findings reinforceresearchers' beliefs that mismatch repair has broad impact on human tumorcell production.

"This study extends results that have been observed in tissue culturecells to human tumors in animals," said Paul Modrich, PhD, a HowardHughes investigator in biochemistry at Duke and lead author of the study."It renders it likely that this drug resistance is also a significanteffect in cancer patients"

Dr. Henry Friedman, chief of pediatric neuro-oncology at Duke and primaryinvestigator of the study funded by the National Institutes of Health,said the research may lead to more effective treatment of GBM.

The Major Problem

"The major problem in the treatment of cancer is drug resistance,"Friedman said. "Tumor cells become resistant, or could be resistantat diagnosis. The cells escape the effects of the drug, repopulate, andthe patient ultimately succumbs to the tumor. If we can determine the mechanismsof 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 treatedthe tumors with procarbazine. Though procarbazine is a frontline drug treatment,most patients ultimately develop resistance to it and it ceases to checktumor growth. The tumors growing on mice developed resistance to the drugafter nine serial treatments, giving the researchers a way to study theresistance mechanism.

In the normal sequence of cell replication, the attached compounds alertthe mismatch repair mechanism in the cell that a mutation has occurred,according to Friedman. That triggers a "toxic event," and ultimatedestruction of the tumor cell.

"What we found was that the resistant tumor cells had a mutationin mismatch repair that was not present in the 'parent' tumor-the tumorgraft that didn't seem to be resistant to drugs at first. We think theresulting deficiency led to the resistance to procarbazine and other methylators."Friedman said.

This summer, Friedman and Modrich are studying the mismatch repair activityin malignant GBM. If the findings from the xenograft tumors bear out, clinicalapplication could begin in trials next year, Friedman said.

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