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【medical-news】【资讯翻译】如何克服他末昔芬耐药性

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http://www.sciencedaily.com/releases/2011/11/111113141409.htm

认领翻译的战友请跟帖注明“认领本文翻译，48小时内未完成，请其他战友认领”

In the last three decades, thousands of women with breast cancer have taken the drug tamoxifen, only to discover that the therapy doesn't work, either because their tumors do not respond to the treatment at all, or because they develop resistance to it over time. Now researchers at the University of California, San Francisco (UCSF) have discovered the molecular basis for tamoxifen resistance and found a potential way to defeat it.

On Nov. 13, 2011, at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, UCSF oncologist Pamela Munster, MD, and her colleagues presented the results of clinical studies and laboratory experiments that show how some tumors resist tamoxifen and how this resistance can be overcome by administering a second class of drugs.

"Understanding the mechanism of tamoxifen resistance and how to defeat it may help a large number of women with hormone-resistant breast cancer," said Munster. "It may lead quickly to new, more effective treatment strategies and may help to identify biomarkers to help to gauge whether or not someone will respond to treatment in the first place."

Tamoxifen Resistance and Breast Cancer The National Cancer Institute estimates that more than 200,000 Americans are diagnosed with breast cancer every year. It is the second leading cause of cancer death among American women, claiming more than 40,000 lives in 2009 alone.

About 65 percent of women with breast cancer have tumors that, when examined in biopsies, show signs of co-opting a naturally occurring molecule in the human body called the estrogen receptor. This receptor helps to stimulate the proliferation and growth of cells -- something that is normally tightly controlled in the body.

Tumors can use the machinery of this receptor to stimulate the unregulated growth and proliferation of cancer cells. Doctors have known for decades that this is one of the main drivers of breast cancer, and elevated levels of estrogen receptor is something oncologists look for when they take tumor biopsies.

Tamoxifen, which blocks the estrogen receptor, is the front-line treatment for premenopausal women whose breast cancer biopsies show elevated levels of the receptor. It can be something of a wonder drug when it works, inhibiting cancer growth and shrinking tumors without the same side effects as chemotherapy.

However, tamoxifen only works in half the women to whom it is prescribed. It may not work in some women because they may have forms of cancer in which the estrogen receptor does not actually play a central role. However, many women taking tamoxifen acquire resistance to it. Their tumors respond to the treatment at first, but then the cancer rebounds and develops the ability to proliferate and grow even when the estrogen receptor is blocked.

While doctors have documented cases of tamoxifen resistance in the clinic for decades, nobody knew exactly how the cells were able to acquire resistance. Many scientists thought that genetics were to blame -- certain variations in one's DNA that would pass from parents to children and make one more likely to develop a tamoxifen-resistant form of breast cancer. According to Munster, that is not the case.

"We always thought that resistance was genetic," said Munster. "But now we have discovered that cells have a way of developing resistance by means of epigenetic modification."

Epigenetics is a general phenomenon in biology that explains how some cells, tissues, and whole organisms can acquire traits that go beyond mere genetic differences. Rather than genes being mutated or changed and then passed on to offspring, which is the domain of genetics, epigenetic changes are not in the genes themselves but in their levels of expression and activity.

Queen bees, for instance, are genetically identical to worker bees, but they are much larger and characteristically quite different. Genes don't account for these differences -- epigenetics does. Queens start out life the same as workers, but they are fed a steady diet of chemicals in their food that alter the levels of expression and activity of their genes, and over time these changes account for their queenly form.

According to the research Munster and her colleagues are presenting this week, it is a similar epigenetic story that accounts for tamoxifen resistance. They discovered that when cancer cells are fed tamoxifen, they sometimes respond by elevating expression of a gene known as AKT.

AKT is a "survival" gene that in normal situations helps to stimulate growth and proliferation of cells and prevent cells from dying. In breast cancer, however, it can become overactive and confer resistance by allowing the cancer cells to continue to use the estrogen receptor even in the presence of tamoxifen.

The good news clinically, said Munster, is that several existing compounds known as histone deacetylase inhibitors directly target AKT. Two of these are already approved by the U.S. Food and Drug Administration for treating a rare type of lymphoma. Several more are actively under development and at least one is in early clinical trials, said Munster.

She and her colleagues showed that when cells in the laboratory are fed these histone deacytalase inhibitors, their levels of AKT are knocked back. Giving the same cells tamoxifen at the same time dramatically curtails the ability of the cells to proliferate.

In clinical studies published earlier this year, Munster and her colleagues also showed that taking both drugs together can reverse tamoxifen resistance.

This approach will have to prove safe and effective in additional, large-scale clinical trials before it becomes generally available.

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2011-11-14 10:58 浏览 : 1036 回复 : 4

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riset 编辑于 2011-11-14 13:28

• 山东一乡镇卫生院院长荣获全国脱贫攻坚先进个人荣誉称号

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认领本文翻译，48小时内未完成，请其他战友认领

2011-11-14 10:59

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• 2021内科主治73道全是病例分析题

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In the last three decades, thousands ofwomen with breast cancer have taken the drug tamoxifen, only to discover thatthe therapy doesn't work, either because their tumors do not respond to thetreatment at all, or because they develop resistance to it over time. Nowresearchers at the University of California, San Francisco (UCSF) havediscovered the molecular basis for tamoxifen resistance and found a potentialway to defeat it.

在过去的三十年中，数以千计的乳腺癌女性患者服用了他莫昔芬，但该药并没有发挥应有的功效。原因可能是：乳腺癌患者体内的肿瘤组织对他莫昔芬的治疗完全没有反应或是随着时间的推移，患者产生了耐药性。如今，加州大学旧金山分校（UCSF）的研究人员已经发现机体产生他莫昔芬耐药的分子基础，并且找到了一条可能克服这种耐药性的方法。

On Nov. 13, 2011, at the AACR-NCI-EORTCInternational Conference: Molecular Targets and Cancer Therapeutics, UCSFoncologist Pamela Munster, MD, and her colleagues presented the results ofclinical studies and laboratory experiments that show how some tumors resisttamoxifen and how this resistance can be overcome by administering a secondclass of drugs.

在2011年11月13日的AACR-NCI-EORTC国际会议——分子靶标和肿瘤治疗上，加州大学旧金山分校的肿瘤学家——Pamela Munster（MD）和她的同事提交了临床研究和实验室实验结果，这些结果显示了一些肿瘤是如何抵抗他莫昔芬的治疗以及患者通过服用另外一类药物是如何克服这种耐药性的。

"Understanding the mechanism oftamoxifen resistance and how to defeat it may help a large number of women withhormone-resistant breast cancer," said Munster. "It may lead quicklyto new, more effective treatment strategies and may help to identify biomarkersto help to gauge whether or not someone will respond to treatment in the firstplace."

Munster说：“了解他莫昔芬产生耐药的机制以及知晓如何克服这种耐药性也许对激素抵抗的广大乳腺癌女性患者有莫大的帮助，这项研究的成果很可能发展成为一个新的、更有效的治疗策略，可能有助于鉴定生物标记物以帮助衡量是否患者在第一时间对治疗有反应。

Tamoxifen Resistance and Breast Cancer TheNational Cancer Institute estimates that more than 200,000 Americans arediagnosed with breast cancer every year. It is the second leading cause ofcancer death among American women, claiming more than 40,000 lives in 2009alone.

国家癌症研究所估计每年超过200,000名美国人被诊断患有乳腺癌。乳腺癌是导致美国女性癌症患者死亡的第二大因素，据称在2009年死亡人数就已经超过了40,000.

About 65 percent of women with breastcancer have tumors that, when examined in biopsies, show signs of co-opting anaturally occurring molecule in the human body called the estrogen receptor.This receptor helps to stimulate the proliferation and growth of cells --something that is normally tightly controlled in the body.

大约有65%的乳腺癌女性患者在活检检查的时候，结果呈现出人体内自然形成的分子——雌激素受体的信号。这种雌激素受体有助于刺激细胞的增殖和生长，一般正常情况下这种雌激素受体在体内是被严格控制的。

Tumors can use the machinery of thisreceptor to stimulate the unregulated growth and proliferation of cancer cells.Doctors have known for decades that this is one of the main drivers of breastcancer, and elevated levels of estrogen receptor is something oncologists lookfor when they take tumor biopsies.

肿瘤可以使用这种受体刺激肿瘤细胞不受控制的增长和增殖。医生们了解到这一点已经有几十年了，他们认为这是乳腺癌发生发展的主要驱动力之一，雌激素受体水平的升高与否是一些肿瘤学家在进行肿瘤活检时必看的指标。

Tamoxifen, which blocks the estrogenreceptor, is the front-line treatment for premenopausal women whose breastcancer biopsies show elevated levels of the receptor. It can be something of awonder drug when it works, inhibiting cancer growth and shrinking tumorswithout the same side effects as chemotherapy.

绝经前妇女在乳房癌活检时，结果显示患者体内的雌激素受体升高。而他莫昔芬通过阻断雌激素受体，是治疗绝经前妇女乳腺癌患者的一线治疗手段。这时他莫昔芬是一个奇特的药物，它起作用的同时（抑制肿瘤生长、缩小肿瘤体积）并不像化疗那样会产生类似的副作用。

However, tamoxifen only works in half thewomen to whom it is prescribed. It may not work in some women because they mayhave forms of cancer in which the estrogen receptor does not actually play acentral role. However, many women taking tamoxifen acquire resistance to it.Their tumors respond to the treatment at first, but then the cancer reboundsand develops the ability to proliferate and grow even when the estrogen receptoris blocked.

然而，他莫昔芬只对一半的乳腺癌女性患者有效，它对某些女性患者却没有疗效，比如他莫昔芬对那些体内雌激素受体不起主要作用的乳腺癌女性患者就没有治疗效果。然而，很多女性在服用他莫昔芬后，机体产生了耐药性。起初，这些女性患者对他莫昔芬的治疗是有反应的，但即使雌激素受体被阻断抑制一段时间后，肿瘤也会出现反弹、重新获得增殖生长能力，也就是出现了所谓的他莫昔芬耐药性。

While doctors have documented cases oftamoxifen resistance in the clinic for decades, nobody knew exactly how thecells were able to acquire resistance. Many scientists thought that geneticswere to blame -- certain variations in one's DNA that would pass from parentsto children and make one more likely to develop a tamoxifen-resistant form ofbreast cancer. According to Munster, that is not the case.

虽然医生提出他莫昔芬耐药抵抗的临床案例已经有数十年了，但没有人真正了解肿瘤细胞为何能获得这种耐药特性。许多研究者认为是基因的缘由，一个人的DNA发生某些变化后，这种变化将会遗传给孩子们，使得他们更容易患上耐他莫昔芬的乳腺癌。据Munster的观念，她不认同这种说法，认为情况并非如此。

"We always thought that resistance wasgenetic," said Munster. "But now we have discovered that cells have away of developing resistance by means of epigenetic modification."

Munster说：“我们经常认为耐药是遗传引起的，但现在我们已经证实了肿瘤细胞获得耐药性是通过表观遗传修饰的方式来实现的。”

Epigenetics is a general phenomenon inbiology that explains how some cells, tissues, and whole organisms can acquiretraits that go beyond mere genetic differences. Rather than genes being mutatedor changed and then passed on to offspring, which is the domain of genetics,epigenetic changes are not in the genes themselves but in their levels ofexpression and activity.

表观遗传是一个生物学中普遍的现象，这一学说解释了一些细胞、组织和整个生物体是如何获得超出单纯的遗传差异的特征性状。不同于基因突变或改变后，传递给后代，表观遗传的改变并不在于基因本身发生了变化，而是这些基因的表达和活性水平发生了变化。

Queen bees, for instance, are geneticallyidentical to worker bees, but they are much larger and characteristically quitedifferent. Genes don't account for these differences -- epigenetics does.Queens start out life the same as workers, but they are fed a steady diet ofchemicals in their food that alter the levels of expression and activity oftheir genes, and over time these changes account for their queenly form.

例如：蜂后、工蜂的基因相同，但蜂后体型更大，其特点余工蜂完全不同。基因并不能解释这种差异的原因，但表观遗传学可以。蜂后出生时是与工蜂一样的，但他们一直食用着的某些食物，这些食物中的化学物质改变了她们体内基因的表达和活性水平，随着时间的推移，这些变化导致了蜂王形态上的变化。

According to the research Munster and hercolleagues are presenting this week, it is a similar epigenetic story thataccounts for tamoxifen resistance. They discovered that when cancer cells arefed tamoxifen, they sometimes respond by elevating expression of a gene knownas AKT.

根据本周Munster和她的同事呈现的研究内容表明：表观遗传的变化可能是出现他莫昔芬耐药性的原因。他们发现，当癌细胞给予他莫昔芬后，它们有时作出反应是AKT基因表表达的升高。

AKT is a "survival" gene that innormal situations helps to stimulate growth and proliferation of cells andprevent cells from dying. In breast cancer, however, it can become overactiveand confer resistance by allowing the cancer cells to continue to use theestrogen receptor even in the presence of tamoxifen

Akt是一个“生存”的基因，该基因在正常情况下有助于刺激细胞的生长和扩散，防止细胞死亡。然而，在乳腺癌中，即使运用他莫昔芬阻断雌激素受体后，AKT的过度活跃也会赋予癌细胞耐药特性，使得这些肿瘤细胞能持续利用雌激素受体

The good news clinically, said Munster, isthat several existing compounds known as histone deacetylase inhibitorsdirectly target AKT. Two of these are already approved by the U.S. Food andDrug Administration for treating a rare type of lymphoma. Several more areactively under development and at least one is in early clinical trials, saidMunster.

Munster说，好消息是被称为组蛋白去乙酰酶抑制剂的几个现有化合物的直接靶标就是AKT。其中两个已经被美国食品和药物管理局批准用于治疗罕见的淋巴瘤。其他几个都在积极开展研究，并且其中至少有一个已经进入了早期临床试验阶段。

She and her colleagues showed that whencells in the laboratory are fed these histone deacytalase inhibitors, theirlevels of AKT are knocked back. Giving the same cells tamoxifen at the sametime dramatically curtails the ability of the cells to proliferate.

她和她的同事发现，在实验室中给予这些细胞组蛋白去乙酰化酶抑制剂后，细胞的Akt水平被抑制。上述同样的细胞在同样的时间点给予他莫昔芬后，细胞的增殖能力被显著抑制。

In clinical studies published earlier thisyear, Munster and her colleagues also showed that taking both drugs togethercan reverse tamoxifen resistance.

在今年早些时候发表的的临床研究中，Munster和她的同事们还表明：一起服用这两种药物可以扭转他莫昔芬耐药性。

This approach will have to prove safe andeffective in additional, large-scale clinical trials before it becomesgenerally available.

这种做法要进行额外的、大规模的临床试验证明安全、有效后，才能被广泛运用。

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请适当编译

2011-11-14 13:17

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yingtiao 编辑于 2011-11-14 14:36

• 因疯狂敛财，哈尔滨第一医院原院长孟庆刚被开除党籍

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在过去的三十年中，数以千计的乳腺癌女性患者服用了他莫昔芬，但该药并没有发挥应有的功效。原因可能是：乳腺癌患者体内的肿瘤组织对他莫昔芬的治疗完全没有反应或是随着时间的推移，患者产生了耐药性。如今，加州大学旧金山分校（UCSF）的研究人员已经发现机体产生他莫昔芬耐药的分子基础，并且找到了一条可能克服这种耐药性的方法。

在2011年11月13日的AACR-NCI-EORTC国际会议——分子靶标和肿瘤治疗上，加州大学旧金山分校的肿瘤学家——Pamela Munster（MD）和她的同事提交了临床研究和实验室实验结果，这些结果显示了一些肿瘤是如何抵抗他莫昔芬的治疗以及患者通过服用另外一类药物是如何克服这种耐药性的。

Munster说：“了解他莫昔芬产生耐药的机制以及知晓如何克服这种耐药性也许对激素抵抗的广大乳腺癌女性患者有莫大的帮助，这项研究的成果很可能发展成为一个新的、更有效的治疗策略，可能有助于鉴定生物标记物以帮助衡量是否患者在第一时间对治疗有反应。

国家癌症研究所估计每年超过200,000名美国人被诊断患有乳腺癌。乳腺癌是导致美国女性癌症患者死亡的第二大因素，据称在2009年死亡人数就已经超过了40,000.

大约有65%的乳腺癌女性患者在活检检查的时候，结果呈现出人体内自然形成的分子——雌激素受体的信号。这种雌激素受体有助于刺激细胞的增殖和生长，一般正常情况下这种雌激素受体在体内是被严格控制的。

肿瘤可以使用这种受体刺激肿瘤细胞不受控制的增长和增殖。医生们了解到这一点已经有几十年了，他们认为这是乳腺癌发生发展的主要驱动力之一，雌激素受体水平的升高与否是一些肿瘤学家在进行肿瘤活检时必看的指标。

绝经前妇女在乳房癌活检时，结果显示患者体内的雌激素受体升高。而他莫昔芬通过阻断雌激素受体，是治疗绝经前妇女乳腺癌患者的一线治疗手段。这时他莫昔芬是一个奇特的药物，它起作用的同时（抑制肿瘤生长、缩小肿瘤体积）并不像化疗那样会产生类似的副作用。

然而，他莫昔芬只对一半的乳腺癌女性患者有效，它对某些女性患者却没有疗效，比如他莫昔芬对那些体内雌激素受体不起主要作用的乳腺癌女性患者就没有治疗效果。然而，很多女性在服用他莫昔芬后，机体产生了耐药性。起初，这些女性患者对他莫昔芬的治疗是有反应的，但即使雌激素受体被阻断抑制一段时间后，肿瘤也会出现反弹、重新获得增殖生长能力，也就是出现了所谓的他莫昔芬耐药性。

虽然医生提出他莫昔芬耐药抵抗的临床案例已经有数十年了，但没有人真正了解肿瘤细胞为何能获得这种耐药特性。许多研究者认为是基因的缘由，一个人的DNA发生某些变化后，这种变化将会遗传给孩子们，使得他们更容易患上耐他莫昔芬的乳腺癌。据Munster的观念，她不认同这种说法，认为情况并非如此。

Munster说：“我们经常认为耐药是遗传引起的，但现在我们已经证实了肿瘤细胞获得耐药性是通过表观遗传修饰的方式来实现的。”

表观遗传是一个生物学中普遍的现象，这一学说解释了一些细胞、组织和整个生物体是如何获得超出单纯的遗传差异的特征性状。不同于基因突变或改变后，传递给后代，表观遗传的改变并不在于基因本身发生了变化，而是这些基因的表达和活性水平发生了变化。

例如：蜂后、工蜂的基因相同，但蜂后体型更大，其特点余工蜂完全不同。基因并不能解释这种差异的原因，但表观遗传学可以。蜂后出生时是与工蜂一样的，但他们一直食用着的某些食物，这些食物中的化学物质改变了她们体内基因的表达和活性水平，随着时间的推移，这些变化导致了蜂王形态上的变化。

根据本周Munster和她的同事呈现的研究内容表明：表观遗传的变化可能是出现他莫昔芬耐药性的原因。他们发现，当癌细胞给予他莫昔芬后，它们有时作出反应是AKT基因表表达的升高。

Akt是一个“生存”的基因，该基因在正常情况下有助于刺激细胞的生长和扩散，防止细胞死亡。然而，在乳腺癌中，即使运用他莫昔芬阻断雌激素受体后，AKT的过度活跃也会赋予癌细胞耐药特性，使得这些肿瘤细胞能持续利用雌激素受体

Munster说，好消息是被称为组蛋白去乙酰酶抑制剂的几个现有化合物的直接靶标就是AKT。其中两个已经被美国食品和药物管理局批准用于治疗罕见的淋巴瘤。其他几个都在积极开展研究，并且其中至少有一个已经进入了早期临床试验阶段。

她和她的同事发现，在实验室中给予这些细胞组蛋白去乙酰化酶抑制剂后，细胞的Akt水平被抑制。上述同样的细胞在同样的时间点给予他莫昔芬后，细胞的增殖能力被显著抑制。

在今年早些时候发表的的临床研究中，Munster和她的同事们还表明：一起服用这两种药物可以扭转他莫昔芬耐药性。

这种做法要进行额外的、大规模的临床试验证明安全、有效后，才能被广泛运用。

2011-11-14 14:45

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