The failure of chemotherapy to stop glioblastoma may be linked to a
deficiency in DNA repair capability in the cell, according to Duke University
Medical Center researchers.
In a study reported in 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, PhD, 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 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 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. 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.
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.
"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."
Friedman said.
This summer, Friedman and Modrich are studying the mismatch repair activity
in malignant GBM. If the findings from the xenograft tumors bear out, clinical
application could begin in trials 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.