最近杜克大学医学院研究人员发现，在接受放射性治疗后，癌症干细胞能够通过活化一种辅助其继续无限生长的“修复开关”，抵制放射波对脑瘤的伤害。此发现为攻克脑瘤等癌症对于放射治疗的抗性开辟了新的道路。研究详细结果刊登于10月18日Nature电子版。
通过在动物和培养细胞中的实验，研究人员发现在接受放射性治疗后，细胞中一种叫做“DNA损伤检验点反应”（DNA damage checkpoint response）的过程能够帮助癌症干细胞开启自发修复DNA损伤的信号，躲过放射波的袭击。
“近几年来，人们开始怀疑癌症干细胞是恶性肿瘤细胞抵抗放射性治疗的罪魁祸首，” 论文初级调查人、杜克大学副教授Jeremy Rich博士说，“我们首次用实验方法证实了这种推论。”
研究所使用的癌症类型是胶质母细胞瘤（glioblastoma），胶质母细胞瘤（glioblastoma）是一种对放射性等治疗方法有高度抗性并且是致死率极高的脑部肿瘤。尽管入侵性治疗能够杀死大多数癌细胞，但总是有一小部分“幸免遇难”并且常常重新发展为体积更大的癌细胞团。究竟是何种机制赋予这些癌症干细胞与众不同的抗性的？直到最近专家也不能给出一个明确的解释。已知的是这些细胞具有与正常功能性神经干细胞相似的特征。
Rich博士等从神经外科获得胶质母细胞瘤组织，然后将瘤组织分配到两个独立的实验模型中。第一种模型是提取胶质母细胞瘤细胞，进行实验室培养；第二种模型是移植瘤组织到小鼠大脑额叶（frontal lobes）。
研究人员对原始组织中神经胶质瘤干细胞的计数后，对培养基中的细胞和小鼠进行致电离辐射。结果两种模型都显示，胶质瘤干细胞的数量大约上升了四倍。致电离辐射治疗的主要原理是引起细胞遗传物质DNA发生永久性损伤，因此研究人员猜测，胶质瘤干细胞比其它癌症干细胞更能适应放射引起的DNA损伤事件，从而幸存下来并且扩增的更多。
为了证实此推论，研究人员在组织样本中寻找与检测DNA损伤有关的特异蛋白。研究人员在致电离辐射治疗前和治疗后，对两种模型的细胞样本中的“检验DNA损伤”关键蛋白活性进行检验，分析“DNA损伤检验点反应”在治疗前后是否有变化。目的是检测是否放射性治疗后，这些细胞能够通过检验点反应或者其它机制，对DNA损伤进行修复。
结果发现在致电离辐射后，胶质瘤干细胞中的DNA损伤检验点蛋白比其它癌细胞中的检验点蛋白活性高出许多。这种高活化状态导致癌症干细胞更有效地对DNA损伤进行修复，结果在接受放射性治疗后幸存下来。
在另一项实验中，研究人员在和放射治疗前后分别添加药物debromohymenialdisine并且对癌症干细胞计数（已知debromohymenialdisine能够抑制活化过程所需蛋白发挥作用。）结果显示，放射前施加药物对癌症干细胞数量变化影响不大；给药和放射治疗同时进行能够增强癌症干细胞的抗辐射能力。这些发现提示，在进行放射性治疗时附加分子检验点抑制剂，能够摧毁细胞的自我修复能力，提高细胞的死亡率。
“我们的结果说明,癌症干细胞中的一种途径能够提高胶质瘤母细胞的抗放射能力，”
Rich说，“以癌症干细胞DNA损伤检验点反应为靶标的治疗，也许是克服肿瘤抗放射能力，治疗癌症的新希望。”
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."
