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论坛首页  >  医药生命科学动态跟踪   >  肿瘤
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【文摘发布】《新英格兰》最新大牛综述:肿瘤的血管生成

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楼主 chjipe
chjipe
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这个帖子发布于12年零320天前,其中的信息可能已发生改变或有所发展。
Tumor Angiogenesis

The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman's imaginative hypothesis,1 but 33 years would elapse before the first drug developed as an inhibitor of angiogenesis was approved by the Food and Drug Administration (FDA).2,3 This approval was based on the survival benefit observed in a randomized phase 3 trial of first-line treatment of metastatic colorectal cancer; in that trial, bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), was combined with conventional chemotherapy.4 Bevacizumab therapy also increased overall survival in the first-line treatment of advanced non–small-cell lung cancer when used in combination with standard chemotherapy.5 Two other antiangiogenic drugs, sorafenib and sunitinib, have also been approved by the FDA; these are oral small-molecule-receptor tyrosine kinase inhibitors (RTKIs). They target multiple receptor tyrosine kinases, including VEGF receptors and platelet-derived growth factor (PDGF) receptors.6 Sorafenib and sunitinib have been beneficial in the treatment of metastatic renal-cell cancer when used alone.7,8 Sorafenib monotherapy is also active in the treatment of hepatocellular carcinoma9 and was recently approved by the FDA for this indication.

The survival benefits of these treatments are relatively modest (usually measured in months), with the possible exception of the benefits for patients with renal-cell carcinoma. These treatments are also costly10 and have toxic side effects.11,12 These concerns raise the following questions with respect to improving antiangiogenic therapy: How do such drugs work, and how does bevacizumab increase the efficacy of chemotherapy? Several theories have been postulated,13,14,15,16 including the theory that antiangiogenic drugs improve chemotherapy by causing "vessel normalization" in tumors (see Appendix 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). How do tumors become resistant to antiangiogenic drugs? Are there clinically useful markers that can predict the efficacy of this class of drug? Are there promising surrogate pharmacodynamic biomarkers that will help to determine the best dose of a particular agent? Will antiangiogenic RTKIs such as sunitinib or sorafenib consistently enhance the efficacy of chemotherapy? What accounts for the side effects of these agents?11,12

Many recent discoveries have the potential not only to answer some of these questions but also to indicate new therapeutic targets and treatment strategies. The purpose of this review is to summarize a number of these discoveries, made mainly over the past 5 years, and to point out their potential clinical impact.

http://intl-content.nejm.org/cgi/content/full/358/19/2039
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2008-06-01 22:16 浏览 : 10847 回复 : 22
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本人已认领该文编译,48小时后若未提交译文,请其他战友自由认领。
2008-06-02 19:50
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The current era of research in antiangiogenic therapy for cancer began in earnest in 1971 with the publication of Folkman's imaginative hypothesis,1 but 33 years would elapse before the first drug developed as an inhibitor of angiogenesis was approved by the Food and Drug Administration (FDA).2,3 This approval was based on the survival benefit observed in a randomized phase 3 trial of first-line treatment of metastatic colorectal cancer; in that trial, bevacizumab, a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF), was combined with conventional chemotherapy.4 Bevacizumab therapy also increased overall survival in the first-line treatment of advanced non–small-cell lung cancer when used in combination with standard chemotherapy.5 Two other antiangiogenic drugs, sorafenib and sunitinib, have also been approved by the FDA; these are oral small-molecule-receptor tyrosine kinase inhibitors (RTKIs). They target multiple receptor tyrosine kinases, including VEGF receptors and platelet-derived growth factor (PDGF) receptors.6 Sorafenib and sunitinib have been beneficial in the treatment of metastatic renal-cell cancer when used alone.7,8 Sorafenib monotherapy is also active in the treatment of hepatocellular carcinoma9 and was recently approved by the FDA for this indication.
现在关于抗血管生成在肿瘤中的治疗是由Folkman在1971年提出的富有想象力的假说,但是,只到33年后,才有一种真正的血管生成抑制药被FDA批准上市。这个批准是基于一项对于随机的转移性结直肠癌的一线治疗方法的生存率的3期临床试验作出的。在这项实验中,一线的治疗方法是指运用人造的对于VEGF的单克隆抗体,贝伐单抗,和其他的常规的化疗药物。贝伐单抗与常规化疗药物合用时,也同时提高了进展期非小细胞肺癌的一线治疗的生存率。其他两种抗血管生成的药物,sorafenib和sunitinib,也同样被FDA批准了,这些是口服的酪氨酸激酶抑制物的小分子受体(RTKIs)。他们是针对酪氨酸激酶受体的靶向药物,同样也针对于VEGF受体和PGDF受体。Sorafenib和sunitinib单独应用时对于转移性肾细胞癌的有益.运用Sorafenib的单独治疗也同样对肝细胞癌有作用,目前,也被FDA所批准。
The survival benefits of these treatments are relatively modest (usually measured in months), with the possible exception of the benefits for patients with renal-cell carcinoma. These treatments are also costly10 and have toxic side effects.11,12 These concerns raise the following questions with respect to improving antiangiogenic therapy: How do such drugs work, and how does bevacizumab increase the efficacy of chemotherapy? Several theories have been postulated,13,14,15,16 including the theory that antiangiogenic drugs improve chemotherapy by causing "vessel normalization" in tumors (see Appendix 1 of the Supplementary Appendix, available with the full text of this article at www.nejm.org). How do tumors become resistant to antiangiogenic drugs? Are there clinically useful markers that can predict the efficacy of this class of drug? Are there promising surrogate pharmacodynamic biomarkers that will help to determine the best dose of a particular agent? Will antiangiogenic RTKIs such as sunitinib or sorafenib consistently enhance the efficacy of chemotherapy? What accounts for the side effects of these agents?11,12
这项治疗的所提高的生存率也只是有限的(大部分都只测试了几个月),对于肾细胞癌还是带着某种可能的猜测。这项治疗的价格比较高而且有毒性的副作用。这些忧虑都引起了下面几个提高抗血管治疗疗效的问题。这些药物是如何发挥作用的?贝伐单抗是如何提高其他化疗药物的效率的?现在有几种还未证实的理论,包括抗血管生成药物是由于引起了肿瘤中的“血管正常化”去协同其他药物的。(见附录1的补充附录,在www.nejm.org上有全文链接)。肿瘤又是如何对抗血管生成药物产生耐药性的?在临床上,有没有有用的标志物去预测这类药物的疗效?有没有有效的药效学上的生物标记的代替物能够对决定某个药物的最佳剂量?抗血管生成的 RTKIs的药物,比如sunitinib或者sorafenib能够持续地增加化疗的疗效?什么东西能够解决这些药物的副作用?
Many recent discoveries have the potential not only to answer some of these questions but also to indicate new therapeutic targets and treatment strategies. The purpose of this review is to summarize a number of these discoveries, made mainly over the past 5 years, and to point out their potential clinical impact.
许多现在的发现不仅有希望回答上述的某些问题,而且也有可能找出新的治疗靶点和治疗方案。这个综述的目的就是总结近3年来许多这方面的研究,同时指出他们未来的临床影响。

文中红色标记的三处的中文翻译很拗或者不太明白,请大家帮助
2008-06-02 23:22
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1 This approval was based on the survival benefit observed in a randomized phase 3 trial of first-line treatment of metastatic colorectal cancer

2 vessel normalization

3 Are there promising surrogate pharmacodynamic biomarkers that will help to determine the best dose of a particular agent?

不好意思,昨天弄上去的时候没有注意。这三个地方,请大家帮忙,谢谢!
2008-06-03 21:03
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