Some Cancer Cells Survive Drugs

Cancer researchers have found that when tumors are treated with anti-vascular and anti-angiogenesis drugs, they respond by increasing production of pro-survival proteins that allow some of the cancer cells to survive.

Investigators at the University of Southern California (Los Angeles, USA) worked with a xenograft model of human breast cancer. They treated the tumors with either the vascular targeting drug combretastatin A4P or the antiangiogenic drug contortrostatin.

Results published in the July 2005 issue of Cancer Research revealed that the drug treatment, which deprived the tumor cells of both glucose and of oxygen, triggered increased synthesis in the endoplasmic reticulum of the Grp78 promoter and elevation of GRP78 protein (glucose-regulated protein 78) in surviving tumor cells. A panel of human breast cancer cells that had developed resistance to a variety of drug treatment regimens was found to overexpress GRP78. Moreover, suppression of GRP78 through the use of a lentiviral vector that expressed small interfering RNA (siRNA) sensitized human breast cancer cells to the drug etoposide.


"When you look at the successful cancer therapies, they often lose efficacy over time because of resistance in the tumor cells,” said senior author Dr. Amy S. Lee, professor of biochemistry and molecular biology at the University of Southern California. "The majority of patients today die not from a primary tumor, but from a failure of the body to overcome the development of resistance to the drugs that treat that tumor. 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. Then, when the therapy is withdrawn, these surviving cells flourish.”



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