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发表于 2008-7-28 22:57:40 | 显示全部楼层 |阅读模式




New Oral Angiogenesis Inhibitor Offers Potential Nontoxic Therapy For A Wide Range Of Cancers新的口服血管生成抑制剂提供了潜在的无毒治疗多种癌症

The first oral, broad-spectrum angiogenesis inhibitor, specially formulated through nanotechnology, shows promising anticancer results in mice, report researchers from Children’s Hospital Boston.


Findings were published online on June 29 by the journal Nature Biotechnology.结果在网上公布的6月29日由Nature杂志上的生物技术。

Because it is nontoxic and can be taken orally, the drug, called Lodamin, may be useful as a preventive therapy for patients at high risk for cancer or as a chronic maintenance therapy for a variety of cancers, preventing tumors from forming or recurring by blocking the growth of blood vessels to feed them.因为它是无毒,可以采取口头,毒品,所谓lodamin ,可能是有用的作为一种预防性治疗高危患者为癌症或作为一种慢性维修治疗多种癌症,防止肿瘤的形成或再次发生阻断血管生长养活他们。
                Lodamin may also be useful in other diseases that involve aberrant blood-vessel growth, such as age-related macular degeneration and arthritis. lodamin也可能是有用的其他疾病,涉及异常的血管生长,如年龄相关性黄斑变性和关节炎。

Developed by Ofra Benny, PhD, in the Children’s laboratory of the late Judah Folkman, MD, Lodamin is a novel slow-release reformulation of TNP-470, a drug developed nearly two decades ago by Donald Ingber, MD, PhD, then a fellow in Folkman’s lab, and one of the first angiogenesis inhibitors to undergo clinical testing.开发ofra陈木胜,博士,在孩子们的实验室后期犹大福克曼,海事处, lodamin是一种新型的缓释改写, TNP - 470 ,药物开发的近两个十年前由司长ingber ,医学博士,哲学博士,然后一位同行在福克曼的实验室,和第一个血管生成抑制剂进行临床测试。
                In clinical trials, TNP-470 suppressed a surprisingly wide range of cancers, including metastatic cancers, and produced a few complete remissions.在临床试验中, , TNP - 470镇压出奇多种癌症,包括转移性癌症,并制作了一套完整的数减免。
                Trials were suspended in the 1990s because of neurologic side effects that occasionally occurred at high doses, but it remains one of the broadest-spectrum angiogenesis inhibitors known.审判暂停,在20世纪90年代,由于神经系统的副作用,偶尔发生在高剂量,但它仍然是最广泛的频谱血管生成抑制剂众所周知的。

Lodamin appears to retain TNP-470’s potency and broad spectrum of activity, but with no detectable neurotoxicity and greatly enhanced oral availability. lodamin出现的保留, TNP - 470的潜力和广阔的频谱活动,但没有探测到神经毒性,并大大增强了口腔的可用性。
                While a number of angiogenesis inhibitors, such as Avastin, are now commercially available, most target only single angiogenic factors, such as VEGF, and they are approved only for a small number of specific cancers.  In contrast, Lodamin prevented capillary growth in response to every angiogenic stimulus tested.虽然有若干血管生成抑制剂,如阿瓦斯丁,现在在商业上可用的,大多数只针对单一的血管生成因子,如血管内皮生长因子,他们只批准了一小一些具体的癌症。相比之下, lodamin阻止毛细管的增长作出回应每血管生成的刺激考验。
                Moreover, in mouse models, Lodamin reduced liver metastases, a fatal complication of many cancers for which there is no good treatment.此外,在小鼠模型, lodamin减少肝转移,一宗致命的并发症,许多种癌症,为这是没有良好的治疗。

“The success of TNP-470 in Phase I and II clinical trials opened up anti-angiogenesis as an entirely new modality of cancer therapy, along with conventional chemotherapy, radiotherapy and surgical approaches,” says Ingber, now co-interim director of the Vascular Biology Program at Children’s. “的成功, TNP - 470在第一阶段和第二阶段的临床试验开辟了抗血管生成作为一个完全新的模式癌症的治疗,随着传统的化学治疗,放射治疗和外科手术的方法,说: ” ingber ,现在的合作,临时主任血管生物学计划在儿童的。

TNP-470 was first reformulated several years ago by Ronit Satchi-Fainaro, PhD, a postdoctoral fellow in Folkman’s lab, who attached a large polymer to prevent it from crossing the blood-brain barrier (Cancer Cell, March 2005). , TNP - 470首次改在数年前由ronit satchi - fainaro ,博士,博士后研究员在福克曼的实验室,谁重视大聚合物,以防止它穿越血脑屏障(癌细胞, 2005年3月) 。
                That formulation, Caplostatin, has no neurotoxicity and is being developed for clinical trials.这一提法, caplostatin ,没有神经毒性,并正在开发的临床试验。
                However, it must be given intravenously.不过,必须给予静脉注射。

Benny took another approach, attaching two short polymers (PEG and PLA) to TNP-470.陈木胜了另一种做法,注重两个短期聚合物( PEG和解放军) , TNP - 470 。
                Experimenting with polymers of different lengths, she found a combination that formed stable, “pom-pom”-shaped nanoparticles known as polymeric micelles, with TNP-470 at the core.试点与聚合物的不同长度,她发现一个组合,形成稳定, “聚甲醛-聚甲醛”形纳米粒子称为高分子胶束,与, TNP - 470处于核心地位。
                The polymers (both FDA-approved and widely used commercially) protect TNP-470 from the stomach’s acidic environment, allowing it to be absorbed intact when taken orally.聚合物(均经FDA批准的,并广泛应用于商业)保护, TNP - 470 ,从胃的酸性环境,使其能够吸收完整时,采取口头方式。
                The micelles reach the tumor, react with water and break down, slowly releasing the drug.胶束达到肿瘤,反应与水和破裂,缓慢释放药物。

Tested in mice, Lodamin had a significantly increased half-life, selectively accumulated in tumor tissue, blocked angiogenesis, and significantly inhibited primary tumor growth in mouse models of melanoma and lung cancer, with no apparent side effects when used at effective doses.测试在小鼠体内, lodamin了显着增加的半衰期,有选择地积聚在肿瘤组织,阻断血管生成,显着抑制肿瘤生长的小学在小鼠模型黑色素瘤和肺癌,没有明显的副作用,使用时,在有效剂量。
                Subsequent tests suggest that Lodamin retains TNP-470’s unusually broad spectrum of activity.随后的测试表明, lodamin保留, TNP - 470的异常广谱的活动。
                “I had never expected such a strong effect on these aggressive tumor models,” Benny says. “我从来没有预期如此强烈的影响,这些侵略瘤模型, ”陈木胜说。

Notably, Lodamin accumulated in the liver without causing toxicity, preventing liver metastases and prolonging survival.值得注意的是, lodamin累积在肝脏中没有造成毒性,防止肝转移和延长生存。
                “This was one of the most surprising things I saw,” says Benny. “这是其中一个最令人惊讶的事情,我看到了,说: ”陈木胜。
                “When I looked at the livers of the mice, the treated group was almost clean. “当我看到肝脏小鼠,治疗组几乎是清洁。
                In the control group you couldn’t recognize the livers -- they were a mass of tumors.”在对照组中,你可以不承认肝脏-他们大量的肿瘤“ 。

TNP-470 itself has an interesting history. , TNP - 470本身有一个有趣的历史。
                It was derived from fumagillin, a mold with strong anti-angiogenic effects that Ingber discovered accidentally while culturing endothelial cells (the cells that line blood vessels).这是来自fumagillin ,模具与强大的抗血管生成的效果ingber发现意外的同时,培养内皮细胞(细胞线血管) 。
                Ingber noticed that in certain dishes -- those contaminated with the mold -- the cells changed their shape by rounding, a behavior that inhibits capillary cell growth. ingber注意到,在某些菜肴-那些污染与模具-细胞改变其形状由四舍五入,行为,抑制细胞生长的毛细管。
                Ingber cultured the fungus, disregarding lab policy, which called for contaminated culture to be discarded immediately. ingber培养真菌,不顾劳顾会的政策,其中要求受污染的文化,必须立即丢弃。
                He and Folkman later developed TNP-470, a synthetic analog of fumagillin, with the help of Takeda Chemical Industries in Japan (Nature, December 1990).他和福克曼稍后发达, TNP - 470 ,一种合成模拟fumagillin ,借助武田化学工业在日本(的性质, 1990年12月) 。
                It has shown activity against dozens of tumor types, though its mechanism of action is only partly known.它表明,对活动的数十名肿瘤的类型,虽然其作用机制的行动,只是部分众所周知的。

“It’s been an evolution,” says Benny, “from fumagillin to TNP-470 to Caplostatin to Lodamin.” “这是一个演变, ”陈木胜说, “从fumagillin到, TNP - 470 caplostatin ,以lodamin ” 。

Lodamin and Caplostatin have been optioned for clinical development by SynDevRx, Inc., a Cambridge, Mass.-based biotechnology company. lodamin和caplostatin已optioned ,为临床发展syndevrx公司,马萨诸塞州的剑桥为基础的生物技术公司。
                Benny, who is from Israel, coined the name Lodamin from Hebrew.陈木胜,谁是来自以色列,创造的名称lodamin从希伯来文。
                (“Lo dam” means “no blood.”)  She continues to study Lodamin’s effects in other animal models of cancer, and in macular degeneration with Robert D’Amato, MD, PhD, in the Vascular Biology program. ( “劳大坝” ,就是“无血” )她继续研究lodamin的影响,在其他动物模型的癌症,并在性黄斑变性与罗伯特达马托,医学博士,哲学博士,在血管生物学计划。

Folkman, the Lodamin paper’s senior author, died unexpectedly in January, just days after Benny submitted the paper for publication.福克曼, lodamin文件的高级作者,突然死亡在1月,刚刚天之后,陈木胜提交的文件以供出版。
                The paper, a part of his legacy, is dedicated to his memory.该文件的一部分,他的遗产,是专用于他的记忆。

The study was supported in part by the US Department of Defense.这项研究是在支持的一部分,由美国国防部。

Journal reference :


  1. Ofra Benny, Ofer Fainaru, Avner Adini, Flavia Cassiola, Lauren Bazinet, Irit Adini, Elke Pravda, Yaakov Nahmias, Samir Koirala, Gabriel Corfas, Robert J D'Amato & Judah Folkman. An orally delivered small-molecule formulation with antiangiogenic and anticancer activity . Nature Biotechnology , Published online: 29 June 2008 DOI: 10.1038/nbt1415 ofra陈木胜, ofer fainaru , avner adini , ( Flavia cassiola ,劳伦bazinet , irit adini , elke真理报, yaakov nahmias ,萨米尔柯伊拉腊,加布里埃尔corfas ,罗伯特j达马托&犹大福克曼。 口头发表的一小分子的制定与抗血管生成和抗癌活动性质,生物技术 ,在线出版: 2008年6月29日土井: 10.1038/nbt1415

Key(s): angiogenesis Nature Biotechnology anti-angiogenic VEGF关键( ) :血管生成的性质,生物技术抗血管生成血管内皮生长因子

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