Cancer Drug Side Effect Caused by Cell “Pump” Problem
December 07, 2006
Newswise — 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 Children’s Research Hospital. The finding, published this month in the Journal of the National Cancer Institute offers clinicians a way to identify patients who are likely to develop diarrhea as a side effect from taking these drugs, 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 pump—a protein called ABCG2—preventing it from disposing of these drugs.
The protein produced by the gene mutation 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 researchers. The protein 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, the mutant protein 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 protein 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 and senior author of the report. Although high levels of a cancer drug in the cell can increase its killing effect, high levels in the blood can cause side effects. “It’s a balancing act, and knowing which mutation to look for in people will help clinicians identify patients who should have their treatment modified by reducing the dose of the drug or switching to another one,” she said.
The finding was made during a study of patients being treated with gefinitib for non-small-cell lung cancer. The results suggest that other cancer drugs handled by this protein pump pose the threat of side effects to patients as well, according to Baker. “Gefitinib represents a new type of treatment called targeted therapy, which researchers hoped would avoid causing significant side effects,” Baker explained. “Targeted drugs are designed to knock out specific molecules that occur in abnormal cells, while sparing normal cells. But our work showed that people with the (gene) mutation are at increased risk for side effects.”
Since diarrhea and skin toxicity limit the use of this drug in some patients, the researchers looked for a specific variation in the gene that could disrupt the function of this particular protein. Among patients getting this drug, 44 percent with the genetic mutation developed diarrhea after receiving gefitinib, compared to only 12 percent of patients without the mutation developed diarrhea. However, this specific mutation did not cause acne, another side effect of gefitinib.
“Our finding also means that as targeted therapies become common in the years ahead it will be important to have a selection of such drugs so clinicians can choose those that are appropriate to the genetic makeup of the patient,” Baker said.
About St. Jude Children's Research Hospital:
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit http://www.stjude.org.
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December 07, 2006
Newswise — 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 Children’s Research Hospital. The finding, published this month in the Journal of the National Cancer Institute offers clinicians a way to identify patients who are likely to develop diarrhea as a side effect from taking these drugs, 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 pump—a protein called ABCG2—preventing it from disposing of these drugs.
The protein produced by the gene mutation 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 researchers. The protein 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, the mutant protein 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 protein 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 and senior author of the report. Although high levels of a cancer drug in the cell can increase its killing effect, high levels in the blood can cause side effects. “It’s a balancing act, and knowing which mutation to look for in people will help clinicians identify patients who should have their treatment modified by reducing the dose of the drug or switching to another one,” she said.
The finding was made during a study of patients being treated with gefinitib for non-small-cell lung cancer. The results suggest that other cancer drugs handled by this protein pump pose the threat of side effects to patients as well, according to Baker. “Gefitinib represents a new type of treatment called targeted therapy, which researchers hoped would avoid causing significant side effects,” Baker explained. “Targeted drugs are designed to knock out specific molecules that occur in abnormal cells, while sparing normal cells. But our work showed that people with the (gene) mutation are at increased risk for side effects.”
Since diarrhea and skin toxicity limit the use of this drug in some patients, the researchers looked for a specific variation in the gene that could disrupt the function of this particular protein. Among patients getting this drug, 44 percent with the genetic mutation developed diarrhea after receiving gefitinib, compared to only 12 percent of patients without the mutation developed diarrhea. However, this specific mutation did not cause acne, another side effect of gefitinib.
“Our finding also means that as targeted therapies become common in the years ahead it will be important to have a selection of such drugs so clinicians can choose those that are appropriate to the genetic makeup of the patient,” Baker said.
About St. Jude Children's Research Hospital:
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit http://www.stjude.org.
<< Back
