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Cancer drug side effect caused by cell 'pump' problem

A troublesome side effect caused by some cancer drugs appears to be caused by a broken "pump" in the liver that fails to push these medicines into a "drain," according to investigators at St. Jude Childrens Research Hospital. The finding offers clinicians a way to identify patients who are likely to develop diarrhea as a side effect from taking these drugs, the researchers said.

The discovery also has implications for people taking other drugs, since this pump controls the blood levels of many of the prescription drugs on the market. This study is the first to show that a specific gene mutation disables the pumpa protein called ABCG2preventing it from disposing of these drugs. The mutation, a type of alteration called a single nucleotide polymorphism, is designated 421C>A in reference to the specific change in one of the DNA building blocks of the gene.

ABCG2 pushes drugs out of cells and back into the blood, or in the case of the liver, the pump pushes drugs into a tube-like structure called the bile canaliculum, which eventually leads to the intestine, from which it is excreted, according to the researchers. ABCG2 also pumps drugs out of the cells lining the intestine, preventing drugs taken by mouth from flooding into the body. Once past the intestine, blood vessels pick up the drugs and bring them to the liver and other parts of the body.

However, mutant ABCG2 can be less efficient at pushing gefitinib out of cells in the intestine, the researchers noted. A buildup of drug within these cells can cause diarrhea.

The ABCG2 mutation sets up a tradeoff between high levels of drug in the cancer cells and high levels in the blood, according to Sharyn Baker, Pharm.D., Ph.D, associate member of Pharmaceutical Sciences at St. Jude. Although high levels of a cancer drug in the cell can increase its killing effect, high levels in the blood can cause side effects. "Its a balancing act, and knowing which mutation to look for in
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Contact: Bonnie Kourvelas
bonnie.kourvelas@stjude.org
901-495-4815
St. Jude Children's Research Hospital
5-Dec-2006


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