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【drug-news】每日服用阿司匹林可由于过多COX-2而减少结肠癌风险

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Daily Aspirin Cut Risk of Colon Cancers With Excess COX-2
BOSTON, May 23 -- Regular use of aspirin reduced the risk of colon cancer but only in tumors high in an enzyme that promotes cancer growth, researchers here reported. Action Points

Explain to interested patients that in this observational study regular use of aspirin (two tablets a week) appeared to reduce the risk of colon cancer, but only for tumors high in an enzyme that promotes cancer growth.

Tell patients who ask that at this point, no one knows how to identify people who might benefit from aspirin therapy.
Extended use of aspirin cut the risk of colorectal cancers that overexpress cyclooxygenase-2 (COX-2) by almost a third, but not the risk of cancers with weak or absent COX-2 expression, Andrew T. Chan, M.D., M.P.H., of Harvard, and colleagues reported in the May 24 issue of the New England Journal of Medicine.

The significance of the COX-2 target emerged from 2,446,431 person-years of follow-up of 82,911 women in the Nurses' Health Study and 47,363 men in the Health Professionals Follow-up Study. Assessments of Cox-2 expression came from a review of pathology reports.

The investigators identified 636 incident cases of colorectal cancer among users and nonusers of aspirin that were available for analysis of COX-2 expression. Of the tumors, 423 (67%) had moderate or strong COX-2 expression (P for heterogeneity = 0.02).

Aspirin users took at least two standard 325 mg tablets a week or used aspirin at least twice a week.

Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 (multivariate relative risk 0.64; 95% confidence interval, 0.52 to 0.78), the researchers found. It had no effect on tumors with weak or absent expression of Cox-2 (multivariate relative risk, 0.96, CI 0.73 to 1.26).

The age-standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users, compared with 56 per 100,000 person-years among those who did not use aspirin regularly.

In contrast, with absent or weak COX-2 tumors, regular or nonregular use of aspirin made no difference. The rate for cancers with little or no COX-2 expression was 27 per 100,000 person-years among regular aspirin users compared with 28 per 100,000 person years among nonregular aspirin users.

Increasing duration of use and increased aspirin dose were also significant, the researchers said.

A reduction for the risk of COX-2-positive tumors was found with increasing duration of aspirin use (multivariate relative risk 0.59), becoming evident after 10 years, the researchers said. But they found was no statistically significant reduction for the Cox-2-negative tumors.

The fact that the reduction in cancer risk was found only after several years of aspirin use suggests an effect of aspirin on the early stages of colorectal adenoma or cancer, the researchers wrote.

A reduction in the relative risk became most apparent with an intake of more than five tablets a week and was further reduced as the number of tablets (six to 14 or more) increased, but again not for the COX-2-negative tumors.

COX-2 is progressively overexpressed during the stepwise sequence from adenoma to carcinoma, Dr. Chan said. Randomized controlled trials have shown that selective COX-2 inhibitors prevent recurrence of adenoma in patients with a history of adenoma or familial polyposis.

Our study suggests, he said, that the anticancer benefit of aspirin is mediated, at least in part, by inhibition of COX-2. Possibly through production of inflammatory prostaglandins or eicosanoids, COX-2 may regulate angiogenesis, apoptosis, or tumor-cell invasiveness.

Experimental studies have shown that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), especially at high doses, have a range of other potentially antineoplastic actions, suggesting that further work is needed to clarify the effects of these agents and COX-2 (or its downstream effectors) on the development of colorectal cancer, the researchers said.

Study limitations acknowledged by the authors included the fact that the study was observational and aspirin use was self-selected. Thus, among users and nonusers there were small, but statistically significant differences in risk factors, including smoking history, physical activity, and use of multivitamins.

Another limitation, they noted, was the lack of a standardized classification system for COX-2 expression in colorectal cancer. However, in this study, in the overall population, the proportion of tumors that overexpressed COX-2 was similar to that found by other investigators, the researchers said.

These results support the importance of continued investigation into COX-2 and related pathways for the development of new treatments and the potential use of COX-2 as a molecular marker for tailoring chemoprevention in participants with a history of colorectal cancer, the investigators concluded.

In an accompanying editorial, Sanford D. Markowitz, M.D., Ph.D., of Case Western Reserve University in Cleveland, wrote that current thinking ascribes the cancer-preventive activity of aspirin and NSAIDS principally to the ability of COX-2 to block the generation of PGE2, the most abundant colon prostaglandin.

The work of Dr. Chan and his colleagues, Dr. Markowitz said, raises a number of questions. How is the cancer-promoting activity of COX-2 mediated? Is it the only or the best target in the pathway to colon cancer? Can we identify the people who are most likely to benefit from COX-2? Are some established colon cancers responsive to inhibitors of this pathway?

He noted that, given the findings of this study, in which only one-third of colon cancers that are positive for COX-2 are prevented by regular aspirin use, it is necessary to ask whether there are alternative strategies for targeting the COX pathway that are more effective and have lower rates of adverse effects.

Furthermore, Dr. Markowitz said, the study's findings pose the challenge of whether we can identify persons in whom COX inhibitors would have the highest likelihood of conferring protection.

A final caveat, he said, is that the primacy of PGE2 has been extrapolated from murine models. There may remain unexpected features unique to the pathogenesis of human colon cancers and particularly of cancers with the highest levels of COX-2.

The findings of this study, Dr. Markowitz said, "provide powerful support for the role of COX-2 as a key mediator in the development of colon cancer and now pose important questions about the biologic basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2."

The study was supported by grants from the National Cancer Institute, NIH, the Marshall S. Kates Memorial Funds, the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. Dr. Chan reported receiving a career development award from the Glaxo Institute for Digestive Health for an unrelated study. He is a recipient of the American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research Scholar Award and a career development award from NCI. Dr. Markowitz, the editorial writer, reported no potential conflict of interest.
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每日服用阿司匹林可由于过多COX-2而减少结肠癌风险
BOSTON, May 23 -- Regular use of aspirin reduced the risk of colon cancer but only in tumors high in an enzyme that promotes cancer growth, researchers here reported. Action Points
波士顿5月23日--定期使用阿司匹林降低患结肠癌风险,但只是在促进肿瘤生长的酶增高的时候,在这里研究者报道。
Explain to interested patients that in this observational study regular use of aspirin (two tablets a week) appeared to reduce the risk of colon cancer, but only for tumors high in an enzyme that promotes cancer growth.
向感兴趣的患者解释此次的观察研究结果,定期使用阿斯匹林(一周两片)可降低结肠癌的发病风险,但只针对促进肿瘤生长的酶增高时有效。
Tell patients who ask that at this point, no one knows how to identify people who might benefit from aspirin therapy.
在向患者问及这一点时,没有人知道如何辨别那些可能受益阿斯匹林治疗。
Extended use of aspirin cut the risk of colorectal cancers that overexpress cyclooxygenase-2 (COX-2) by almost a third, but not the risk of cancers with weak or absent COX-2 expression, Andrew T. Chan, M.D., M.P.H., of Harvard, and colleagues reported in the May 24 issue of the New England Journal of Medicine.
长期服用阿斯匹林由于环氧合酶(COX-2)的几乎高于3倍的过度表达从而降低结肠癌风险,但这不是说,结肠癌患者没有环氧合酶(COX-2)的表达或者表达较弱,哈佛大学的医学博士Andrew T. Chan和同事在5月24日发行的新英格兰医学杂志报道上说。
The significance of the COX-2 target emerged from 2,446,431 person-years of follow-up of 82,911 women in the Nurses' Health Study and 47,363 men in the Health Professionals Follow-up Study. Assessments of Cox-2 expression came from a review of pathology reports.
通过2,446,431人年数,其中82,911从事卫生护理的女性和47,363名从事卫生专业的男性的随访研究,COX-2的位点出现具有重大意义。对COX-2评估来自病理报告审的回顾性研究。
The investigators identified 636 incident cases of colorectal cancer among users and nonusers of aspirin that were available for analysis of COX-2 expression. Of the tumors, 423 (67%) had moderate or strong COX-2 expression (P for heterogeneity = 0.02).
研究者通过对636例结直肠患者服用阿斯匹林与未服用的比较,分析COX-2的表达有效性。肿瘤患者中有423例(67%)CXO-2有中等度的或者高表达(P的异质性=0.02)。
Aspirin users took at least two standard 325 mg tablets a week or used aspirin at least twice a week.
阿斯匹林使用者一周至少需要用标准含量为325毫克片剂两片,或每周至少使用阿斯匹林两次。
Regular aspirin use conferred a significant reduction in the risk of colorectal cancers that overexpressed COX-2 (multivariate relative risk 0.64; 95% confidence interval, 0.52 to 0.78), the researchers found. It had no effect on tumors with weak or absent expression of Cox-2 (multivariate relative risk, 0.96, CI 0.73 to 1.26).
对比定期服用阿斯匹灵患大肠癌风险显著减少,研究人员发现COX-2高表达 (多元相对危险度0.64;95%置信区间,0.52到0.78)。环氧合酶-2弱表达或不表达对肿瘤没有影响 (多元相对危险度,0.96,ci0.73至1.26).
The age-standardized incidence rate for cancers that overexpressed COX-2 was 37 per 100,000 person-years among regular aspirin users, compared with 56 per 100,000 person-years among those who did not use aspirin regularly.
癌症标准化年龄发病率中COX-2过表达,定期服用阿司匹林每十万人年中有37人表达,相比那些不定期的使用阿斯匹林每十万人年中有56人。
In contrast, with absent or weak COX-2 tumors, regular or nonregular use of aspirin made no difference. The rate for cancers with little or no COX-2 expression was 27 per 100,000 person-years among regular aspirin users compared with 28 per 100,000 person years among nonregular aspirin users.
相反, COX-2不表达或表达较弱的肿瘤,定期或不定期使用阿斯匹林没有差别。定期使用阿斯匹林每十万人年中27人癌症发生率很少或没有COX-2表达,相比那些不定期的使用阿斯匹林每十万人年中有56人癌症发生率患者很少或没有COX-2表达。
Increasing duration of use and increased aspirin dose were also significant, the researchers said.
研究者说,增加使用时间和增加阿司匹林剂量,也都具有重大意义。
A reduction for the risk of COX-2-positive tumors was found with increasing duration of aspirin use (multivariate relative risk 0.59), becoming evident after 10 years, the researchers said. But they found was no statistically significant reduction for the Cox-2-negative tumors.
研究发现增加期服用阿斯匹林时间可以减少肿瘤中COX-2阳性的风险(多元相对危险度0.59),10年后越来越明显,研究人员说。但是他们发现COX-2在肿瘤中的表达阴性并没有显著的统计学意义。
The fact that the reduction in cancer risk was found only after several years of aspirin use suggests an effect of aspirin on the early stages of colorectal adenoma or cancer, the researchers wrote.
研究者写道,事实上, 服用阿斯匹灵减少癌症的风险数年之后才会被发现,且显示阿斯匹林对早期大肠腺瘤或癌有效。
A reduction in the relative risk became most apparent with an intake of more than five tablets a week and was further reduced as the number of tablets (six to 14 or more) increased, but again not for the COX-2-negative tumors.
一周摄入量超过5粒或更多(6至14个或更多)将明显降低相对危险性,但是, COX-2在肿瘤中不在是阴性表达。
COX-2 is progressively overexpressed during the stepwise sequence from adenoma to carcinoma, Dr. Chan said. Randomized controlled trials have shown that selective COX-2 inhibitors prevent recurrence of adenoma in patients with a history of adenoma or familial polyposis.
陈博士说,其顺序从腺瘤向癌COX-2呈渐近性的高表达。随机对照临床试验表明,选择性COX-2抑制剂可剂防止腺瘤史患者腺瘤或家族性息肉病复发。
Our study suggests, he said, that the anticancer benefit of aspirin is mediated, at least in part, by inhibition of COX-2. Possibly through production of inflammatory prostaglandins or eicosanoids, COX-2 may regulate angiogenesis, apoptosis, or tumor-cell invasiveness.
我们的研究显示,他说,阿斯匹林的抗癌作用是间接的,至少有一部分通过抑制COX-2,可能是通过致炎因子前列腺素或类花生酸类物质起作用,COX-2可能调剂血管生成,细胞凋亡,或肿瘤细胞侵袭。
Experimental studies have shown that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDS), especially at high doses, have a range of other potentially antineoplastic actions, suggesting that further work is needed to clarify the effects of these agents and COX-2 (or its downstream effectors) on the development of colorectal cancer, the researchers said.
实验研究表明,阿斯匹林和类固醇非甾体抗炎药物,尤其是大剂量时,有一系列其他潜在的抗癌作用,提醒我们将来的工作需要去证实在结肠直肠癌发展中的这些因子和COX-2(或其下游区效应因子)的作用,研究人员说到。
Study limitations acknowledged by the authors included the fact that the study was observational and aspirin use was self-selected. Thus, among users and nonusers there were small, but statistically significant differences in risk factors, including smoking history, physical activity, and use of multivitamins.
作者承认研究有局限性的事实,其中包括这项研究的观测和服用阿斯匹林是自我选择。而且,服用者与非服用者人数都较少,但在统计上有显著差异的风险因素,包括吸烟史,体力活动,并利用多种维生素。
Another limitation, they noted, was the lack of a standardized classification system for COX-2 expression in colorectal cancer. However, in this study, in the overall population, the proportion of tumors that overexpressed COX-2 was similar to that found by other investigators, the researchers said.
他们指出,另一个限制因素是,对COX-2在大肠癌中的表达缺乏一个规范的分类体系。然而,在这项研究中,通过其他研究者的调查,在总人口中COX-2在肿瘤中的过度表达结果相似,研究人员说。
These results support the importance of continued investigation into COX-2 and related pathways for the development of new treatments and the potential use of COX-2 as a molecular marker for tailoring chemoprevention in participants with a history of colorectal cancer, the investigators concluded.
这些结果,对继续调查COX-2和开发新的治疗和潜在使用COX-2作为分子标记剪裁化学预防相关途径为有大肠癌病史的参与者具有重要的支持性,调查者说。
In an accompanying editorial, Sanford D. Markowitz, M.D., Ph.D., of Case Western Reserve University in Cleveland, wrote that current thinking ascribes the cancer-preventive activity of aspirin and NSAIDS principally to the ability of COX-2 to block the generation of PGE2, the most abundant colon prostaglandin.
在克利夫兰西部病例储备大学的医学博士桑福德丁维兹在随后社论中说,当前普遍认为阿斯匹林和非甾体类药物预防癌症的能力是因为COX-2阻断PGE2的产生,在大肠癌中含有丰富的结肠前列腺素。
The work of Dr. Chan and his colleagues, Dr. Markowitz said, raises a number of questions. How is the cancer-promoting activity of COX-2 mediated? Is it the only or the best target in the pathway to colon cancer? Can we identify the people who are most likely to benefit from COX-2? Are some established colon cancers responsive to inhibitors of this pathway?
与陈博士一起工作的同事Markowitz 说,新增了许多问题。COX-2究竟是怎样的间接促进癌症的发展?它是否惟一的或是最佳的作用位点在结肠癌的发生过程中?人们是否能够从COX-2获得最大的好处?某些既定的结肠癌迅速抑制这条通路?
He noted that, given the findings of this study, in which only one-third of colon cancers that are positive for COX-2 are prevented by regular aspirin use, it is necessary to ask whether there are alternative strategies for targeting the COX pathway that are more effective and have lower rates of adverse effects.
他指出,由于这项研究的结果发现,其中只有三分之一COX-2的呈阳性反应的大肠癌被定期服用阿斯匹林阻断,因此,有必要寻找是否针对COX通路更有效和更低利率的负面效应的替代策略。
Furthermore, Dr. Markowitz said, the study's findings pose the challenge of whether we can identify persons in whom COX inhibitors would have the highest likelihood of conferring protection.
此外,Markowitz博士说,该项研究结果形成了一个挑战是否我们能够辨别人们使用环氧化酶抑制剂后具有很高的保护效应。
A final caveat, he said, is that the primacy of PGE2 has been extrapolated from murine models. There may remain unexpected features unique to the pathogenesis of human colon cancers and particularly of cancers with the highest levels of COX-2.
他说, PGE2最终结论,首先是从鼠类模型被推断出的,结肠癌患者发病机理可能仍有意想不到的特点,特别高水平的COX-2表达的癌症患者。
The findings of this study, Dr. Markowitz said, "provide powerful support for the role of COX-2 as a key mediator in the development of colon cancer and now pose important questions about the biologic basis and clinical implications of discovering differences between colon cancers that express high or low levels of COX-2."
这项研究的结果,谢维兹说,“ COX-2的作为主要调剂者在结肠癌发展与现在构成重大问题的生物学基础及临床意义显示COX-2在结肠癌表达的水平高低,提供强有力的支持作用” 。

The study was supported by grants from the National Cancer Institute, NIH, the Marshall S. Kates Memorial Funds, the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. Dr. Chan reported receiving a career development award from the Glaxo Institute for Digestive Health for an unrelated study. He is a recipient of the American Gastroenterological Association/Foundation for Digestive Health and Nutrition Research Scholar Award and a career development award from NCI. Dr. Markowitz, the editorial writer, reported no potential conflict of interest.
在来自美国国家癌症研究所,国立卫生研究院,马绍尔国会kates纪念基金贝内特的家庭基金,有针对性的治疗研究中心,及娱乐事业基金会全国大肠癌研究联盟的研究赠款的支持下, 陈博士接到由葛兰素研究所消化健康无相关的研究机构颁发的职业生涯研制奖。他是一个受美国胃肠病学会/消化健康与营养基金会研究学者奖和生涯发展奖由国立癌症研究所。markowitz博士的主编,没有发现潜在的利益冲突。

本文共编译2,011字
每日服用阿司匹林可由于过多COX-2而减少结肠癌风险
波士顿5月23日--定期使用阿司匹林降低患结肠癌风险,但只是在促进肿瘤生长的酶增高的时候,在这里研究者报道。
向感兴趣的患者解释此次的观察研究结果,定期使用阿斯匹林(一周两片)可降低结肠癌的发病风险,但只针对促进肿瘤生长的酶增高时有效。
在向患者问及这一点时,没有人知道如何辨别那些可能受益阿斯匹林治疗。
长期服用阿斯匹林由于环氧合酶(COX-2)的几乎高于3倍的过度表达从而降低结肠癌风险,但这不是说,结肠癌患者没有环氧合酶(COX-2)的表达或者表达较弱,哈佛大学的医学博士Andrew T. Chan和同事在5月24日发行的新英格兰医学杂志报道上说。
通过2,446,431人年数,其中82,911从事卫生护理的女性和47,363名从事卫生专业的男性的随访研究,COX-2的位点出现具有重大意义。对COX-2评估来自病理报告审的回顾性研究。
研究者通过对636例结直肠患者服用阿斯匹林与未服用的比较,分析COX-2的表达有效性。肿瘤患者中有423例(67%)CXO-2有中等度的或者高表达(P的异质性=0.02)。
阿斯匹林使用者一周至少需要用标准含量为325毫克片剂两片,或每周至少使用阿斯匹林两次。
对比定期服用阿斯匹灵患大肠癌风险显著减少,研究人员发现COX-2高表达 (多元相对危险度0.64;95%置信区间,0.52到0.78)。环氧合酶-2弱表达或不表达对肿瘤没有影响 (多元相对危险度,0.96,ci0.73至1.26).
癌症标准化年龄发病率中COX-2过表达,定期服用阿司匹林每十万人年中有37人表达,相比那些不定期的使用阿斯匹林每十万人年中有56人。
相反, COX-2不表达或表达较弱的肿瘤,定期或不定期使用阿斯匹林没有差别。定期使用阿斯匹林每十万人年中27人癌症发生率很少或没有COX-2表达,相比那些不定期的使用阿斯匹林每十万人年中有56人癌症发生率患者很少或没有COX-2表达。
研究者说,增加使用时间和增加阿司匹林剂量,也都具有重大意义。
研究发现增加期服用阿斯匹林时间可以减少肿瘤中COX-2阳性的风险(多元相对危险度0.59),10年后越来越明显,研究人员说。但是他们发现COX-2在肿瘤中的表达阴性并没有显著的统计学意义。
研究者写道,事实上, 服用阿斯匹灵减少癌症的风险数年之后才会被发现,且显示阿斯匹林对早期大肠腺瘤或癌有效。
一周摄入量超过5粒或更多(6至14个或更多)将明显降低相对危险性,但是, COX-2在肿瘤中不在是阴性表达。
陈博士说,其顺序从腺瘤向癌COX-2呈渐近性的高表达。随机对照临床试验表明,选择性COX-2抑制剂可剂防止腺瘤史患者腺瘤或家族性息肉病复发。
我们的研究显示,他说,阿斯匹林的抗癌作用是间接的,至少有一部分通过抑制COX-2,可能是通过致炎因子前列腺素或类花生酸类物质起作用,COX-2可能调剂血管生成,细胞凋亡,或肿瘤细胞侵袭。
实验研究表明,阿斯匹林和类固醇非甾体抗炎药物,尤其是大剂量时,有一系列其他潜在的抗癌作用,提醒我们将来的工作需要去证实在结肠直肠癌发展中的这些因子和COX-2(或其下游区效应因子)的作用,研究人员说到。
作者承认研究有局限性的事实,其中包括这项研究的观测和服用阿斯匹林是自我选择。而且,服用者与非服用者人数都较少,但在统计上有显著差异的风险因素,包括吸烟史,体力活动,并利用多种维生素。
他们指出,另一个限制因素是,对COX-2在大肠癌中的表达缺乏一个规范的分类体系。然而,在这项研究中,通过其他研究者的调查,在总人口中COX-2在肿瘤中的过度表达结果相似,研究人员说。
这些结果,对继续调查COX-2和开发新的治疗和潜在使用COX-2作为分子标记剪裁化学预防相关途径为有大肠癌病史的参与者具有重要的支持性,调查者说。
在克利夫兰西部病例储备大学的医学博士桑福德丁维兹在随后社论中说,当前普遍认为阿斯匹林和非甾体类药物预防癌症的能力是因为COX-2阻断PGE2的产生,在大肠癌中含有丰富的结肠前列腺素。
与陈博士一起工作的同事Markowitz 说,新增了许多问题。COX-2究竟是怎样的间接促进癌症的发展?它是否惟一的或是最佳的作用位点在结肠癌的发生过程中?人们是否能够从COX-2获得最大的好处?某些既定的结肠癌迅速抑制这条通路?
他指出,由于这项研究的结果发现,其中只有三分之一COX-2的呈阳性反应的大肠癌被定期服用阿斯匹林阻断,因此,有必要寻找是否针对COX通路更有效和更低利率的负面效应的替代策略。
此外,Markowitz博士说,该项研究结果形成了一个挑战是否我们能够辨别人们使用环氧化酶抑制剂后具有很高的保护效应。
他说, PGE2最终结论,首先是从鼠类模型被推断出的,结肠癌患者发病机理可能仍有意想不到的特点,特别高水平的COX-2表达的癌症患者。
这项研究的结果,谢维兹说,“ COX-2的作为主要调剂者在结肠癌发展与现在构成重大问题的生物学基础及临床意义显示COX-2在结肠癌表达的水平高低,提供强有力的支持作用” 。
在来自美国国家癌症研究所,国立卫生研究院,马绍尔国会kates纪念基金贝内特的家庭基金,有针对性的治疗研究中心,及娱乐事业基金会全国大肠癌研究联盟的研究赠款的支持下, 陈博士接到由葛兰素研究所消化健康无相关的研究机构颁发的职业生涯研制奖。他是一个受美国胃肠病学会/消化健康与营养基金会研究学者奖和生涯发展奖由国立癌症研究所。markowitz博士的主编,没有发现潜在的利益冲突。
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