最近杜克大學(xué)醫(yī)學(xué)院研究人員發(fā)現(xiàn),，在接受放射性治療后,，癌癥干細(xì)胞能夠通過活化一種輔助其繼續(xù)無限生長的“修復(fù)開關(guān)”,，抵制放射波對腦瘤的傷害,。此發(fā)現(xiàn)為攻克腦瘤等癌癥對于放射治療的抗性開辟了新的道路,。研究詳細(xì)結(jié)果刊登于10月18日Nature電子版,。
通過在動物和培養(yǎng)細(xì)胞中的實驗,，研究人員發(fā)現(xiàn)在接受放射性治療后，細(xì)胞中一種叫做“DNA損傷檢驗點反應(yīng)”（DNA damage checkpoint response）的過程能夠幫助癌癥干細(xì)胞開啟自發(fā)修復(fù)DNA損傷的信號,，躲過放射波的襲擊,。
“近幾年來，人們開始懷疑癌癥干細(xì)胞是惡性腫瘤細(xì)胞抵抗放射性治療的罪魁禍?zhǔn)祝?rdquo; 論文初級調(diào)查人,、杜克大學(xué)副教授Jeremy Rich博士說,，“我們首次用實驗方法證實了這種推論。”
研究所使用的癌癥類型是膠質(zhì)母細(xì)胞瘤（glioblastoma）,，膠質(zhì)母細(xì)胞瘤（glioblastoma）是一種對放射性等治療方法有高度抗性并且是致死率極高的腦部腫瘤,。盡管入侵性治療能夠殺死大多數(shù)癌細(xì)胞，但總是有一小部分“幸免遇難”并且常常重新發(fā)展為體積更大的癌細(xì)胞團,。究竟是何種機制賦予這些癌癥干細(xì)胞與眾不同的抗性的,？直到最近專家也不能給出一個明確的解釋。已知的是這些細(xì)胞具有與正常功能性神經(jīng)干細(xì)胞相似的特征,。
Rich博士等從神經(jīng)外科獲得膠質(zhì)母細(xì)胞瘤組織,，然后將瘤組織分配到兩個獨立的實驗?zāi)Ｐ椭小５谝环N模型是提取膠質(zhì)母細(xì)胞瘤細(xì)胞,，進行實驗室培養(yǎng),；第二種模型是移植瘤組織到小鼠大腦額葉（frontal lobes）。
研究人員對原始組織中神經(jīng)膠質(zhì)瘤干細(xì)胞的計數(shù)后,，對培養(yǎng)基中的細(xì)胞和小鼠進行致電離輻射。結(jié)果兩種模型都顯示,，膠質(zhì)瘤干細(xì)胞的數(shù)量大約上升了四倍,。致電離輻射治療的主要原理是引起細(xì)胞遺傳物質(zhì)DNA發(fā)生永久性損傷，因此研究人員猜測，膠質(zhì)瘤干細(xì)胞比其它癌癥干細(xì)胞更能適應(yīng)放射引起的DNA損傷事件,，從而幸存下來并且擴增的更多,。
為了證實此推論，研究人員在組織樣本中尋找與檢測DNA損傷有關(guān)的特異蛋白,。研究人員在致電離輻射治療前和治療后,，對兩種模型的細(xì)胞樣本中的“檢驗DNA損傷”關(guān)鍵蛋白活性進行檢驗，分析“DNA損傷檢驗點反應(yīng)”在治療前后是否有變化,。目的是檢測是否放射性治療后,，這些細(xì)胞能夠通過檢驗點反應(yīng)或者其它機制，對DNA損傷進行修復(fù),。
結(jié)果發(fā)現(xiàn)在致電離輻射后,，膠質(zhì)瘤干細(xì)胞中的DNA損傷檢驗點蛋白比其它癌細(xì)胞中的檢驗點蛋白活性高出許多。這種高活化狀態(tài)導(dǎo)致癌癥干細(xì)胞更有效地對DNA損傷進行修復(fù),，結(jié)果在接受放射性治療后幸存下來,。
在另一項實驗中，研究人員在和放射治療前后分別添加藥物debromohymenialdisine并且對癌癥干細(xì)胞計數(shù)（已知debromohymenialdisine能夠抑制活化過程所需蛋白發(fā)揮作用,。）結(jié)果顯示,，放射前施加藥物對癌癥干細(xì)胞數(shù)量變化影響不大；給藥和放射治療同時進行能夠增強癌癥干細(xì)胞的抗輻射能力,。這些發(fā)現(xiàn)提示,，在進行放射性治療時附加分子檢驗點抑制劑，能夠摧毀細(xì)胞的自我修復(fù)能力,，提高細(xì)胞的死亡率,。
“我們的結(jié)果說明,癌癥干細(xì)胞中的一種途徑能夠提高膠質(zhì)瘤母細(xì)胞的抗放射能力，”
Rich說,，“以癌癥干細(xì)胞DNA損傷檢驗點反應(yīng)為靶標(biāo)的治療,，也許是克服腫瘤抗放射能力，治療癌癥的新希望,。”
英文原文：
New Genomic Tests Guide Choice of Chemotherapy in Cancer Patients
Scientists at Duke University's Institute for Genome Sciences & Policy have developed a panel of genomic tests that analyzes the unique molecular traits of a cancerous tumor and determines which chemotherapy will most aggressively attack that patient's cancer.
In experiments reported in the November 2006 issue of the journal Nature Medicine, the researchers applied the genomic tests to cells derived from tumors of cancer patients. They found that the tests were 80 percent accurate in predicting which drugs would be most effective in killing the tumor.
The Duke team plans to begin a clinical trial of the genomic tests in breast cancer patients next year.
The new tests have the potential to save lives and reduce patients' exposure to the toxic side effects of chemotherapy, said Anil Potti, M.D., the study's lead investigator and an assistant professor of medicine in the Duke Institute for Genome Sciences & Policy. The tests are designed to help doctors select and initiate treatment with the best drug for a patient's tumor instead of trying various drugs in succession until the right one is found, Potti said.
"Over 400,000 patients in the United States are treated with chemotherapy each year, without a firm basis for which drug they receive," said Joseph Nevins, Ph.D., the study's senior investigator and a professor of genetics at the Duke Institute for Genome Sciences & Policy. "We believe these genomic tests have the potential to revolutionize cancer care by identifying the right drug for each individual patient."
The tests work by scanning thousands of genes from a patient's tumor to produce a "genomic" profile of the tumor's molecular makeup. Using the genomic tests in cancer cells in the laboratory, the scientists successfully matched the right chemotherapy for the patient's tumor type. The scientists were then able to validate their predictions against patients' actual clinical outcomes.
Doctors currently must use a trial-and-error approach to chemotherapy, trying various established drugs to see which has an effect. As a result, patients often undergo multiple toxic therapies in a process that places patients' lives at risk as their conditions worsen with each treatment.
"Chemotherapy will likely continue to be the backbone of many anticancer treatment strategies," said Potti. "With the new test, we think that physicians will be able to personalize chemotherapy in a way that should improve outcomes."
The first clinical trial will compare how well patients respond to chemotherapy when it is guided by the new genomic predictors versus when it is selected by physicians in the usual trial-and-error manner. The researchers anticipate that they will enroll approximately 120 patients with breast cancer in the study. Subsequent clinical trials will enroll hundreds of patients with lung and ovarian cancer, Potti said.
If proven effective, the tests could be applied to all cancers in which chemotherapy is given, not just breast, lung, and ovarian cancer, Potti said.
The researchers developed the new tests through a process that included analyzing the activity of thousands of genes in cells taken from the tumors of cancer patients.
In using the test, scientists extract the genetic molecule "messenger RNA" from a cancer patient's tumor cells. Messenger RNA translates a gene's DNA code into proteins that run the cell's activities. Hence, it is a barometer of a gene's activity level inside the cell.
The scientists then label the messenger RNA with fluorescent tags and place the labeled molecules on a tiny glass slide, called a gene chip, which binds to segments of DNA representing the tens of thousands of genes in the genome.
When scanned with special light, the fluorescent RNA emits a telltale luminescence that demonstrates how much RNA is present on the chip, and this reading indicates which genes are most active in a given tumor. The scientists use this signature of gene expression in the cancer cells to predict which chemotherapeutic agent will be most powerful in treating the specific tumor.
In the current study, funded by the National Institutes of Health, the researchers assessed the tests' ability to predict how patients with breast and ovarian cancer and leukemia responded to various anticancer drugs. They found that the tests predicted the clinical response to chemotherapy with 80 percent accuracy.
"Importantly, we believe this research can improve the efficiency of chemotherapy without changing the drugs currently used in standard practice," Nevins said. "Rather, the tests simply provide an approach to better selection, within a repertoire of available drugs."
