When unopposed, this mechanism can give cancer cells the ultimate victory. "The induction of these protective genes is a survival mechanism that allows a small number of cells to become resistant to the chemotherapy's effects," Lee explains. "Then, when the therapy is withdrawn, these surviving cells flourish."
Lee and her colleagues showed, in a model of human breast cancer in which the tumor cells were treated with anti-vascular and anti-angiogenesis drugs called, respectively, combretastatin A4P and contortrostatin, that GRP78 levels were greatly increased only in those tumor cells that survived the drug's action. "We further show that GRP78 is overexpressed in a panel of human breast cancer cells that has developed resistance to a variety of drug treatment regimens," the paper's authors add.
Finally, Lee and her colleagues showed that tumor cells in which the GRP78 gene is suppressed are unable to mount a resistance to the chemotherapy drug etoposide.
"Our studies imply that anti-vascular and anti-angiogenesis therapy that results in severe glucose and oxygen deprivation will induce GRP78 expression that could lead to drug resistance," the authors conclude.
This is not a death knell for the highly popular and successful anti-vascular and anti-angiogenesis drugs, however. Lee believes that there is a way around this particular type of cellular defense.
"I do not think the problem is unfixable," she says. "One approach is to create combination therapies using drugs to counteract stress proteins like GRP78."
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Contact: Jon Weiner
jon.weiner@usc.edu
323-442-2830
University of Southern California
1-Jul-2005