圣犹大儿童研究医院的研究人员发现，有些抗癌药物造成麻烦的副作用，是由于细胞泵浦的问题，造成这些药物无法进入肝脏中。这项发现可以提供临床医师辨认出可能发生腹泻副作用的患者。
这项研究显示，一个特殊基因ABCG2的突变导致泵浦蛋白质失去能力，使肝脏无法处理这些药物。ABCG2基因的多样性遗传多样性可以用来解释ABCG2底物药物代谢动力学的多样性。
ABCG2的功能是将有毒物质和外来化学物及时转运出细胞而进入血液中，从而保护人体的某些组织，或是在肝脏中，将药物唧打至胆小管中，最后再进入肠道而排泄出。
ABCG2也可以将药物从肠道内衬的细胞中唧打出，避免口服的抗癌药物流入体内。一但通过肠道，血管就会吸收药物并带入肝脏和身体其它部位。
但是，如果ABCG2突变，将gefitinib唧打出肠道内衬细胞的效果就会不佳，因此药物积累在这些细胞中而导致患者腹泻。ABCG2突变的患者以Gefitinib治疗后，发生腹泻的比例高达百分之44，而没有突变的患者发生腹泻的比例只有百分之12。这项研究结果发表于12月6 日的Journal of the National Cancer Institute中。
英文原文：
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 Children抯 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 pump梐 protein called ABCG2梡reventing 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. "It抯 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 the ABCG2 pump pose the threat of side effects to patients as well, according to Baker. She is the senior author of a report on this study that appears in the December 6 issue of the Journal of the National Cancer Institute.
"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 ABCG2 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 ABCG2 gene that could disrupt the function of the ABCG2 protein.
Among patients getting this drug, 44 percent of 124 individuals with the mutation in the ABCG2 gene developed diarrhea after receiving gefitinib; only 12 percent of 108 patients without the mutation developed diarrhea. However, this specific mutation did not cause acne, another side of 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.
Baker was at The Sidney Kimmel comprehensive Cancer Center at Johns Hopkins when she worked on this project.
