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【medical-news】一种新的癌症治疗方法有望用于临床

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http://www.nytimes.com/2009/06/29/health/research/29drug.html?_r=1&ref=health

New Cancer Treatment Shows Promise in Testing

By NICHOLAS WADE
Published: June 28, 2009
A new method of attacking cancer cells, developed by researchers in Australia, has proved surprisingly effective in animal tests.

The method is intended to sidestep two major drawbacks of standard chemotherapy: the treatment’s lack of specificity and the fact that cancer cells often develop resistance.

In one striking use of the method, reported online Sunday in Nature Biotechnology, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment; the untreated mice were dead after a month.

The lead researchers, Jennifer A. MacDiarmid and Himanshu Brahmbhatt, say their company, EnGeneIC of suburban Sydney, has achieved a similar outcome in dogs with advanced brain cancer. “We have been treating more than 20 dogs and have spectacular results,” Dr. Brahmbhatt said. “Pretty much every dog has responded and some are in remission.” These experiments have not yet been published.

Cancer experts who were not involved with the research say that the new method is of great interest, but that many treatments that work well in laboratory mice turn out to be ineffective in patients.

Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, called the method “a creative and promising line of research,” but noted the general odds against success.

“Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients,” he said.

The EnGeneIC researchers said they had conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors in three Melbourne hospitals next month. They said they had discussed licensing their technology with large pharmaceutical companies and others.

Stephen H. Friend, head of cancer research at Merck until early this year, said he had been following EnGeneIC’s work for more than a year, and praised the company for trying a method that others had written off without trying.

“I consider the approach is remarkable and more than intriguing,” said Dr. Friend, who is now at Sage Bionetworks in Seattle. But he warned that cancer cells are very versatile and can “evolve around any pressure you put on them,” so that no single approach is likely to afford a cure.

The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins.

The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells.

No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor.

The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry.

What also helps direct the minicells toward tumors, the EnGeneIC researchers say, is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites.

The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated, Dr. Brahmbhatt said.

In the experiments reported Sunday, EnGeneIC treated cancer-ridden mice with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. The gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents.

After the toxin-expelling gene had been knocked down in the tumor cells, the EnGeneIC researchers injected a second wave of minicells, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy.

The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether.

“The technology looks very good,” said Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island. It provides a general method of delivering chemicals to tumors, he said, especially those that are usually degraded in the bloodstream.

Dr. Stillman, who has advised EnGeneIC and is a co-author of its report, said the minicells could be particularly helpful for delivering silencing RNAs, a promising new class of drug that is rapidly destroyed in the body unless protected.

Though the minicells can be varied to attack different receptors and to import any gene of interest on elements called plasmids, the method still has several hurdles to jump.

Robert M. Hoffman, of the University of California, San Diego, said that the minicells were “good strategy and good science” but that the researchers had implanted the human tumors under the mice’s skin, a position from which they do not usually spread through the body. So the experiments do not answer the question of whether minicells can attack metastasized cancer, he said.

Dr. Hoffman, who is president of AntiCancer Inc., has obtained striking remissions with metastasized cancers in mice by treating them with salmonella bacteria. The bacteria have been engineered to lack two kinds of amino acid, which makes them unable to grow in normal tissues. In cancer cells, however, where the missing amino acids are in more plentiful supply, the bacteria are highly virulent and kill the cells.

The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission. Both Dr. Hoffman’s method and the minicells, in different ways, revisit these old observations. Both may face special scrutiny from regulators concerned at the prospect of putting bacteria into people.

Dr. Hoffman said his studies with the defective bacteria were going well and that his company might be ready to start a safety test in patients in two years if it can find a good partner. Use of bacteria in cancer “is an old story but there is definitely a lot of promise there,” he said.

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• 2020主治考试难度加大？

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粗译：
A new method of attacking cancer cells, developed by researchers in Australia, has proved surprisingly effective in animal tests.
澳大利亚的研究人员们开发了一种新的攻击癌症细胞的方法，这种方法在动物实验中表现了令人惊讶的效果。
The method is intended to sidestep two major drawbacks of standard chemotherapy: the treatment’s lack of specificity and the fact that cancer cells often develop resistance.
这种方法能够避免标准化疗中两个主要的缺点：一般的治疗手段缺乏针对性和癌症细胞会有耐药性。
In one striking use of the method, reported online Sunday in Nature Biotechnology, mice were implanted with a human uterine tumor that was highly aggressive and resistant to many drugs. All of the treated animals were free of tumor cells after 70 days of treatment; the untreated mice were dead after a month.
星期天发表在《自然生物技术》网络版上的文章中说，在一个实验中，给小鼠转接对很多药物有耐药性的人恶性子宫肿瘤，所有接受这种令人振奋的方法治疗的小鼠在经过70天的治疗后肿瘤细胞消失了，而没有接受治疗的小鼠则在一个月后死亡。
The lead researchers, Jennifer A. MacDiarmid and Himanshu Brahmbhatt, say their company, EnGeneIC of suburban Sydney, has achieved a similar outcome in dogs with advanced brain cancer. “We have been treating more than 20 dogs and have spectacular results,” Dr. Brahmbhatt said. “Pretty much every dog has responded and some are in remission.” These experiments have not yet been published.
这项研究的领导者Jennifer A. MacDiarmid和Himanshu Brahmbhatt说他们的公司EnGeneIC已经在恶性脑癌的狗模型中得到相似的结果，这家公司位于悉尼的郊外。“我们对超过20只狗进行了治疗，得到了这个令人振奋的结果，” Brahmbhatt博士说。“基本上对每只狗都有效，有些甚至是被治愈。”这些实验结果还没有被发表。
Cancer experts who were not involved with the research say that the new method is of great interest, but that many treatments that work well in laboratory mice turn out to be ineffective in patients.
没有参加这项研究的癌症专家们对这项研究很感兴趣，但是他们说许多在小鼠实验中效果明显的的治疗方法对病人却没有什么作用。
Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, called the method “a creative and promising line of research,” but noted the general odds against success.
Bert Vogelstein是约翰．霍普金斯大学的癌症研究领导者，他称这种方法为“一种创造性的和充满希望的系列研究”，但同时也注意到了成功背后存在的风险。
“Unfortunately our track record shows that far less than 1 percent of our promising approaches actually make the grade in patients,” he said.
“不幸的是我们的记录显示之前有希望的方法中真正能有效治疗病人的远远低于1%。”
The EnGeneIC researchers said they had conducted successful safety tests in a large number of monkeys and will start safety trials in patients with all kinds of solid tumors in three Melbourne hospitals next month. They said they had discussed licensing their technology with large pharmaceutical companies and others.
EnGeneIC公司的研究者们说他们已经对大量的猴子进行了成功的安全实验，并将于下月在墨尔本的三家医院进行各种实体肿瘤的安全实验。他们说他们已经就授权大型医药公司使用这项技术的问题进行过讨论。
Stephen H. Friend, head of cancer research at Merck until early this year, said he had been following EnGeneIC’s work for more than a year, and praised the company for trying a method that others had written off without trying.
Stephen H. Friend曾于今年早些时候担任Merck肿瘤研究负责人，他称自己跟随EnGeneIC公司的这项研究超过一年，夸赞他们有勇气去尝试其他人看都不看就否决的方法。
“I consider the approach is remarkable and more than intriguing,” said Dr. Friend, who is now at Sage Bionet works in Seattle. But he warned that cancer cells are very versatile and can “evolve around any pressure you put on them,” so that no single approach is likely to afford a cure.
“我认为这项研究非常值得关注，而不是什么所谓的阴谋，” Friend博士说，他现在在西雅图为贤哲生物网工作。但是他也警告说癌症细胞是万能的，“能抵抗任何我们给予他们的压力，”没有什么方法能够单独治疗癌症。
The EnGeneIC method uses minicells to deliver a variety of agents to tumor cells, including both anticancer toxins and mechanisms for suppressing the genes that make tumors resistant to toxins.
EnGeneIC公司的方法是利用微细胞开发各种抗肿瘤的药物，包括抗肿瘤毒素和抑制使肿瘤能够抵抗毒素的基因的机制。
The minicells are generated from mutant bacteria which, each time they divide, pinch off small bubbles of cell membrane. The minicells can be loaded with chemicals and coated with antibodies that direct them toward tumor cells.
微细胞是由突变细菌生成，这种突变细菌在每次分裂时都会填堵上细胞膜上的缝隙。这种微细胞内部装着药物，外部包裹着能引导他们靠近肿瘤细胞的抗体。
No tumor cell, so far as is known, produces a specific surface molecule for toxins to act on. But 80 percent of solid tumors have their cell surfaces studded with extra-large amounts of the receptor for a particular hormone, known as epidermal growth factor.
就目前所知，没有肿瘤细胞有能使毒素作用的特殊表面分子。但是80%的实体肿瘤的细胞表面点缀着极其大量的一种叫表皮生长因子的特殊激素的受体。
The minicells can be coated with an antibody that recognizes this receptor, so they are more likely to attach themselves to tumors than to the normal cells of the body. The tumor cells engulf and destroy the minicells, a standard defense against bacteria, and in doing so are exposed to whatever cargo the minicells carry.
微细胞可以给自己包裹上能识别这种受体的抗体，所以他们接近肿瘤组织的概率要比机体正常细胞大的多。肿瘤细胞吞噬并分解这种微细胞，这是对细菌的正常防卫程序，但是这样做恰恰释放了微细胞所携带的货物。
What also helps direct the minicells toward tumors, the EnGeneIC researchers say, is that the blood vessels around tumors tend to be leaky, and the minicells are small enough to leave the circulation at the leak sites.
同样能让微细胞进入肿瘤组织的是肿瘤组织周围的血管上的漏洞，微细胞体积之小足够使它在漏洞处进入肿瘤组织。
The minicells do not seem to be highly provocative to the immune system, even though they are made of bacterial cell membrane. The reason may be that the provocative parts of the membrane are masked by antibodies with which the minicells are coated, Dr. Brahmbhatt said.
微细胞不会引起免疫系统的高度反应，尽管它们是由细菌细胞膜组成的。原因可能是细胞膜的应激部被包裹微细胞的抗体遮盖了。Brahmbhatt博士说。
In the experiments reported Sunday, EnGeneIC treated cancer-ridden mice with two waves of minicells. The first wave contained an agent that suppressed an important gene for toxin resistance. The gene makes a protein that pumps toxin out of cells, and is a major cause of the resistance that tumors often develop toward chemotherapeutic agents.
在星期天报道的研究中，EnGeneIC的研究人员给予荷瘤鼠两波微细胞。第一波微细胞中含有一种能抑制一个重要的抵抗病毒的基因的药物。这种基因能生成一种蛋白质，这种蛋白质能把毒素排出细胞外，这也是肿瘤细胞对化疗药物产生抗药性的主要原因。
After the toxin-expelling gene had been knocked down in the tumor cells, the EnGeneIC researchers injected a second wave of minicells, each loaded with half a million molecules of doxorubicin, a toxin used in chemotherapy.
当肿瘤细胞内的排毒基因被抑制后，研究人员给予第二波微细胞。这波微细胞内含有50万分子的在化疗中使用的毒素阿霉素。
The two-wave treatment arrested tumor growth in mice implanted with either human colon or human breast tumors, and enabled mice with drug-resistant human uterine tumors to eliminate the tumors altogether.
两波治疗能够抑制移植到小鼠身上的人结肠和乳腺肿瘤的生长，也能抑制抗药性人子宫肿瘤的生长。
“The technology looks very good,” said Bruce Stillman, president of the Cold Spring Harbor Laboratory on Long Island. It provides a general method of delivering chemicals to tumors, he said, especially those that are usually degraded in the bloodstream.
“这个技术看上去非常棒，” Bruce Stillman说，他是长岛冷泉港实验室的负责人。它提供了一种将药物输送到肿瘤组织的通行办法，尤其是那些容易在血循环过程中降解的药物。
Dr. Stillman, who has advised EnGeneIC and is a co-author of its report, said the minicells could be particularly helpful for delivering silencing RNAs, a promising new class of drug that is rapidly destroyed in the body unless protected.
Stillman博士是EnGeneIC公司的顾问，也是这篇报道的协作作者。他说微细胞对输送沉默RNA很有帮助，沉默RNA是一种新的有希望的药物，但是在体内没有保护的话就很容易被破坏。
Though the minicells can be varied to attack different receptors and to import any gene of interest on elements called plasmids, the method still has several hurdles to jump.
虽然微细胞可以以各种形式攻击不同的受体，并把任何感兴趣的基因插入到叫做质粒的元件上，但是这种方法仍有几个障碍需要跨越。
Robert M. Hoffman, of the University of California, San Diego, said that the minicells were “good strategy and good science” but that the researchers had implanted the human tumors under the mice’s skin, a position from which they do not usually spread through the body. So the experiments do not answer the question of whether minicells can attack metastasized cancer, he said.
Robert M. Hoffman来自San Diego的California大学，他认为微细胞是“极好的策略，绝妙的科学方法”，但是研究人员采用的方法将肿瘤移植到小鼠的皮下部位，皮下往往不容易产生转移，所以目前还不知道是否对转移性癌症有效果。
Dr. Hoffman, who is president of AntiCancer Inc., has obtained striking remissions with metastasized cancers in mice by treating them with salmonella bacteria. The bacteria have been engineered to lack two kinds of amino acid, which makes them unable to grow in normal tissues. In cancer cells, however, where the missing amino acids are in more plentiful supply, the bacteria are highly virulent and kill the cells.
Hoffman博士是AntiCancer公司的董事长，他能够利用沙门杆菌有效的缓解小鼠转移性癌。沙门杆菌中含有两种让沙门杆菌不能生存在正常组织中的氨基酸，但是在肿瘤细胞中这两种氨基酸是大量存在的，所以他们移除了沙门杆菌中的这两种氨基酸，这样沙门杆菌就能在肿瘤细胞中大量生长并杀死肿瘤细胞。
The idea of treating cancer with bacteria goes back to the 19th century, when physicians noticed that cancer patients who became infected sometimes enjoyed a remission. Both Dr. Hoffman’s method and the minicells, in different ways, revisit these old observations. Both may face special scrutiny from regulators concerned at the prospect of putting bacteria into people.
利用细菌治疗癌症的方法要回溯到19世纪，那时侯的医生发现感染了细菌的癌症患者往往会缓解病情。Hoffman博士的方法和微细胞方法虽然不同，但是都是延续了这种古老的思路，都将因将细菌和人联系起来而遭受的特别关注。
Dr. Hoffman said his studies with the defective bacteria were going well and that his company might be ready to start a safety test in patients in two years if it can find a good partner. Use of bacteria in cancer “is an old story but there is definitely a lot of promise there,” he said.
Hoffman博士说他的缺陷病毒研究进展不错，如果能找到好的合作者的话，将在两年内进行患者安全测试。利用细菌治疗癌症“是一个古老而又充满希望的方法”，他说。

编译：
澳大利亚的研究人员们开发了一种新的攻击癌症细胞的方法，这种方法在动物实验中效果令人惊讶。这种方法能够避免标准化疗中两个重要缺点：治疗手段缺乏针对性和癌症细胞会有耐药性。
星期天发表在《自然生物技术》网络版上的文章中说，在一个实验中，给小鼠转接对很多药物有耐药性的人恶性子宫肿瘤，所有接受这种令人振奋的方法治疗的小鼠在经过70天的治疗后肿瘤细胞消失了，而没有接受治疗的小鼠则在一个月后死亡。
EnGeneIC公司未发表的研究显示这种方法已经在恶性脑癌的狗模型中得到相似的结果，他们对超过20只狗进行了治疗，基本上对每只狗都有效，有些甚至是被治愈。
也有专家担心许多在小鼠实验中效果明显的的治疗方法对病人却没有什么作用。
EnGeneIC公司的研究者们说他们已经对大量的猴子进行了成功的安全实验，并将于下月在墨尔本的三家医院进行各种实体肿瘤的安全实验。
Stephen H. Friend曾跟随EnGeneIC公司的这项研究超过一年，夸赞他们有勇气去尝试其他人看都不看就否决的方法。但是他也警告说不要过于乐观。
EnGeneIC公司的方法是利用微细胞开发各种抗肿瘤的药物，包括抗肿瘤毒素和抑制使肿瘤能够抵抗毒素的基因的机制。
微细胞是由突变细菌生成，内部装着药物，外部包裹着能引导他们靠近肿瘤细胞的抗体，所以他们接近肿瘤组织的概率要比机体正常细胞大的多。肿瘤细胞吞噬并分解这种微细胞，这是对细菌的正常防卫程序，但是这样做恰恰释放了微细胞所携带的货物。还有一条途径就是肿瘤组织周围的血管上的漏洞，微细胞体积之小足够使它在漏洞处进入肿瘤组织。

微细胞不会引起免疫系统的高度反应。原因可能是细胞膜的应激部被包裹微细胞的抗体遮盖了。报道上说，EnGeneIC的研究人员给予荷瘤鼠两波微细胞。第一波微细胞中含有一种能抑制一个重要的抵抗病毒的基因的药物。这种基因能生成一种蛋白质，这种蛋白质能把毒素排出细胞外，这也是肿瘤细胞对化疗药物产生抗药性的主要原因。当肿瘤细胞内的排毒基因被抑制后，研究人员给予第二波微细胞。这波微细胞内含有50万分子的在化疗中使用的毒素阿霉素。两波治疗能够抑制移植到小鼠身上的人结肠和乳腺肿瘤的生长，也能抑制抗药性人子宫肿瘤的生长。这技术提供了一种将药物输送到肿瘤组织的通行办法，尤其是那些容易在血循环过程中降解的药物，比如沉默RNA。
Robert M. Hoffman认为微细胞技术是“极好的策略，绝妙的科学方法”，但是研究人员采用的方法将肿瘤移植到小鼠的皮下部位，皮下往往不容易产生转移，所以目前还不知道是否对转移性癌症有效果。他能够利用沙门杆菌有效的缓解小鼠转移性癌。沙门杆菌中含有两种让沙门杆菌不能生存在正常组织中的氨基酸，但是在肿瘤细胞中这两种氨基酸是大量存在的，所以他们移除了沙门杆菌中的这两种氨基酸，这样沙门杆菌就能在肿瘤细胞中大量生长并杀死肿瘤细胞。
利用细菌治疗癌症的方法要回溯到19世纪，那时侯的医生发现感染了细菌的癌症患者往往会缓解病情。

2009-07-06 11:09

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crownbiocyc 编辑于 2009-07-07 15:07

• 2020成绩是真是假？？

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应该是不错的方法，有无内行者来评点一下？

2009-07-08 09:28

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anmb1

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Concept of dual sequential therapy (nanocell-mediated delivery of siRNA followed by drug) to treat drug resistant cancers

In a single figure it shows EDVs emerging from the tumor associated leaky vasculature and entering into a tumor microenvironment.
A single tumor cell is depicted which in clockwise segments undergoes the sequential therapy to result in tumor cell death in the last segment.

In brief (clockwise shown by purple arrow):

Segment 1: tumor cells over-expressing, as an example, multi-drug resistance mediating protein (purple) hence preventing drug (red) entry into the cell.

Segment 2: tumor receptor-targeted, siRNA-packaged minicells docking onto tumor cell surface receptor (green).

Segment 3: EDVs endocytosed and degraded in intracellularlysosomes, releasing siRNA into the cytoplasm.

Segment 4: siRNA strands separate and bind to target mRNA (yellow).

Segment 5: Target mRNA cleavage and cell surface showing knockdown of the multi-drug resistance mediating protein (disappearing purple protein).

Segment 6: Tumor receptor-targeted, drug-packaged minicells docking onto the tumor cell surface receptor (green).

Segment 7: EDVs are endocytosed, degraded in lysosomes and releasing the drug into the cytoplasm and nucleus.

Segment 8: Tumor cell is flooded with the drug and the cell crumbles and dies.

(This figure is published in Nature Biotechnology, July 2009.)

2009-07-08 11:30

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anmb1 编辑于 2009-07-08 11:35

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