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    Linda M.Hendershot, PhD

    Understanding drug resistance

    St. Jude researchers have shown that tumor cells become resistant to drugs called topoisomerase poisons by activating a protective response that reduces the amount of the topoisomerase enzymes those drugs target. A report on this work appears in the December 2005 issue of Molecular Pharmacology.

    Mammalian cells have two topoisomerase II enzymes, designated II-alpha and II-beta, which transiently cut doublestranded DNA when the cell needs to access a gene or unravel and duplicate a chromosome before cell division. When topoisomerase poisons disrupt the work of these enzymes, the broken DNA frequently cannot be restored to its normal unbroken state; the presence of this damaged DNA can activate a suicide program called apoptosis, which kills the tumor cell.

    A St. Jude team led by Linda Hendershot, PhD, Genetics and Tumor Cell Biology, and John Nitiss, PhD, Molecular Pharmacology, showed that the limited amount of blood and oxygen available to the tumor cell activates a signaling program called the unfolded protein response (UPR). Under normal circumstances the cell uses this protective response whenever it encounters stresses such as decreased oxygen or nutrients or increased toxins. This program allows the cell to halt certain activities until it can respond appropriately to the stress.

    One result of UPR activation is the temporary suspension of most protein production. During this pause, the cell tries to reduce the amount of unfolded proteins, which otherwise might pose a serious threat to the cell. The St. Jude team showed that activation of the UPR dramatically reduced levels of topoisomerase II-alpha protein and increased the resistance of these cells to topoisomerase II poisons.

    By decreasing the expression of this protein, the cells make themselves more resistant to the drugs that target it, Hendershot said. Activation of the UPR also induces a number of other protective responses that could further contribute to the drug resistance that was observed. “These findings could help us find ways to increase the tumor cell’s sensitivity to these drugs,” she said.

    Other authors of the paper include Miranda Gray, Molecular Pharmacology, and Melissa Mann, Genetics and Tumor Cell Biology.

    Last update: March 2006