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关注低剂量地西他滨联合阿扎胞苷用于抗癌的最新研究

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8163 14 憨豆精神 发表于 2012-3-26 19:58:10 |

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得别人复述消息, 美国约翰·霍普金斯大学医学院最近有关于低剂量地西他滨(DAC)联合阿扎胞苷(AZA)用于抗癌的最新研究,发表在《细胞》杂志,走的是DNA甲基化抑制的路子,该研究称用于非小细胞肺癌和乳腺癌和结肠癌的治疗。
这两种药都是现成的,只是毒性太大,而新的研究发现低剂量可达到治疗目的。究竟他们研究时用过哪些剂量?效果如何?请懂英文的朋友抽空搜索一下看看,说不定是一条很好的路。
我是肿瘤病人,不是肿瘤医生;我的一切意见仅供参考,千万别与正规医嘱等同。
欢迎光顾:(http://blog.sina.com.cn/u/5306366644)

14条精彩回复,最后回复于 2018-12-10 22:59

以马内利  退休老干部 发表于 2012-3-28 01:10:08 | 显示全部楼层
老马识途啊
老马  退休老干部 发表于 2012-3-27 23:36:14 | 显示全部楼层
DAC剂量实验
Decitabine in Treating Patients With Advanced Refractory Solid Tumors or Lymphomas
http://clinicaltrials.gov/ct2/sh ... citabine&rank=8
Drug: Decitabine
Starting dose of 2.5 mg/m^2 intravenously over 1 hour daily days 1-5 and 8-12 for Dose Levels 1-3 and for 5 consecutive days per week of each 4-week cycle for Dose Levels 4 and higher.
个人公众号:treeofhope
又一个五年  大学一年级 发表于 2012-3-27 21:07:33 | 显示全部楼层
本帖最后由 又一个五年 于 2012-3-27 21:50 编辑

The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction, and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical environment, of DNA. Epigenetic activities turn on certain genes and block others,
这种低剂量疗法彻底改变了癌细胞的基因通路,包括那些控制细胞周期、细胞修复、细胞成熟、细胞变异、细胞免于交互作用及细胞死亡的基因通路。尽管在这些各自不同的肿瘤细胞中治疗效果有差异,但科学家们普遍看到癌细胞回复到了一种较正常的状态,最后死亡。这些结果部分是由DNA的基因以外的,或者化学环境的改变引起的。这些基因外的活动使一些基因打开,而又使另一些基因锁住。
(不懂专业,大概意思。)

这样神奇的效果,像是中医说的治到了本?如果不是可逆的,是不意味着癌症要被攻克了?

不管怎样急切想知道临床试验的低药量,能否麻烦我们论坛的在美国的朋友爱姐姐和浮生若水想办法了解到?
憨豆精神  超级版主 发表于 2012-3-27 17:14:55 | 显示全部楼层

谢谢老马!你真厉害,什么都被你搜出来。
你看看能不能进一步找到那两个非小肺癌的临床试验的两药的剂量?这是最关键的,有了剂量,我们就可以同步自行试验。
我是肿瘤病人,不是肿瘤医生;我的一切意见仅供参考,千万别与正规医嘱等同。
欢迎光顾:(http://blog.sina.com.cn/u/5306366644)
老马  退休老干部 发表于 2012-3-26 22:26:46 | 显示全部楼层
上文说关于乳腺癌和肺癌的临床试验已经开始,但我没有搜到。
AZA关于非小肺癌的临床试验只有二个:
Azacitidine and MS-275 in Treating Patients With Recurrent Advanced Non-Small Cell Lung Cancer

Trial of Adjuvant Combined Epigenetic Therapy With 5-azacitidine and Entinostat in Resected Stage I Non-small Cell Lung Cancer Versus Standard Care
个人公众号:treeofhope
老马  退休老干部 发表于 2012-3-26 22:13:28 | 显示全部楼层
Scientists Reprogram Cancer Cells with Low Doses of Epigenetic Drugs

Published: March 22, 2012.  Johns Hopkins Medical Institutions


Experimenting with cells in culture, researchers at the Johns Hopkins Kimmel Cancer Center have breathed possible new life into two drugs once considered too toxic for human cancer treatment. The drugs, azacitidine (AZA) and decitabine (DAC), are epigenetic-targeted drugs and work to correct cancer-causing alterations that modify DNA.
The researchers said the drugs also were found to take aim at a small but dangerous subpopulation of self-renewing cells, sometimes referred to as cancer stem cells, which evade most cancer drugs and cause recurrence and spread.

In a report published in the March 20, 2012, issue of Cancer Cell, the Johns Hopkins team said their study provides evidence that low doses of the drugs tested on cell cultures cause antitumor responses in breast, lung, and colon cancers.

Conventional chemotherapy agents work by indiscriminately poisoning and killing rapidly-dividing cells, including cancer cells, by damaging cellular machinery and DNA. "In contrast, low doses of AZA and DAC may re-activate genes that stop cancer growth without causing immediate cell-killing or DNA damage," says Stephen Baylin, M.D., Ludwig Professor of Oncology and deputy director of the Johns Hopkins Kimmel Cancer Center.

Many cancer experts had abandoned AZA and DAC for the treatment of common cancers, according to the researchers, because they are toxic to normal cells at standard high doses, and there was little research showing how they might work for cancer in general. Baylin and his colleague Cynthia Zahnow, Ph.D., decided to take another look at the drugs after low doses of the drugs showed a benefit in patients with a pre-leukemic disorder called myelodysplastic syndrome (MDS). Johns Hopkins investigators also showed benefit of low doses of the drugs in tests with a small number of advanced lung cancer patients. "This is contrary to the way we usually do things in cancer research," says Baylin, noting that "typically, we start in the laboratory and progress to clinical trials. In this case, we saw results in clinical trials that made us go back to the laboratory to figure out how to move the therapy forward."

For the research, Baylin and Zahnow's team worked with leukemia, breast, and other cancer cell lines and human tumor samples using the lowest possible doses that were effective against the cancers. In all, the investigators studied six leukemia cell lines, seven leukemia patient samples, three breast cancer cell lines, seven breast tumor samples (including four samples of tumors that had spread to the lung), one lung cancer tumor sample, and one colon cancer tumor sample. The team treated cell lines and tumor cells with low-dose AZA and DAC in culture for three days and allowed the drug-treated cells to rest for a week. Treated cells and tumor samples were then transplanted into mice where the researchers observed continued antitumor responses for up to 20 weeks. This extended response was in line with observations in some MDS patients who continued to have anticancer effects long after stopping the drug.

The low-dose therapy reversed cancer cell gene pathways, including those controlling cell cycle, cell repair, cell maturation, cell differentiation, immune cell interaction, and cell death. Effects varied among individual tumor cells, but the scientists generally saw that cancer cells reverted to a more normal state and eventually died. These results were caused, in part, by alteration of the epigenetic, or chemical environment, of DNA. Epigenetic activities turn on certain genes and block others, says Zahnow, assistant professor of oncology and the Evelyn Grolman Glick Scholar at Johns Hopkins.

The research team also tested AZA and DAC's effect on a type of metastatic breast cancer cell thought to drive cancer growth and resist standard therapies. Metastatic cells are difficult to study in standard laboratory tumor models, because they tend to break away from the original tumor and float around in blood and lymph fluids. The Johns Hopkins team re-created the metastatic stem cells' environment, allowing them to grow as floating spheres. "These cells were growing well as spheres in suspension, but when we treated the cells with AZA, both the size and number of spheres were dramatically reduced," says Zahnow.

The precise mechanism of how the drugs work is the focus of ongoing studies by Baylin and his team. "Our findings match evidence from recent clinical trials suggesting that the drugs shrink tumors more slowly over time as they repair altered mechanisms in cells and genes return to normal function and the cells may eventually die," says Baylin.

The results of clinical trials in lung cancer, led by Johns Hopkins' Charles Rudin, M.D., and published late last year in Cancer Discovery, also indicate that the drugs make tumors more responsive to standard anticancer drug treatment. This means, they say, that the drugs could become part of a combined treatment approach rather than a stand-alone therapy and as part of personalized approaches in patients whose cancers fit specific epigenetic and genetic profiles.

Low doses of both drugs are approved by the U.S. Food and Drug Administration for the treatment of MDS and chronic myelomonocytic leukemia (CMML). Clinical trials in breast and lung cancer have begun in patients with advanced disease, and trials in colon cancer are planned.
个人公众号:treeofhope
老马  退休老干部 发表于 2012-3-26 22:08:16 | 显示全部楼层
本帖最后由 老马 于 2012-3-26 22:13 编辑


Azacitidine and decitabine have different mechanisms of action in non-small cell lung cancer cell lines

Aaron N Nguyen1, Paul W Hollenbach1, Normand Richard2, Antonio Luna-Moran1, Helen Brady2, Carla Heise1, Kyle J MacBeth1
1Celgene Corporation, San Francisco, CA, USA; 2Celgene Corporation, San Diego, CA, USA

Abstract: Azacitidine (AZA) and decitabine (DAC) are cytidine azanucleoside analogs with clinical activity in myelodysplastic syndromes (MDS) and potential activity in solid tumors. To better understand the mechanism of action of these drugs, we examined the effects of AZA and DAC in a panel of non-small cell lung cancer (NSCLC) cell lines. Of 5 NSCLC lines tested in a cell viability assay, all were sensitive to AZA (EC50 of 1.8–10.5 µM), while only H1299 cells were equally sensitive to DAC (EC50 of 5.1 µM). In the relatively DAC-insensitive cell line A549, both AZA and DAC caused DNA methyltransferase I depletion and DNA hypomethylation; however, only AZA significantly induced markers of DNA damage and apoptosis, suggesting that mechanisms in addition to, or other than, DNA hypomethylation are important for AZA-induced cell death. Cell cycle analysis indicated that AZA induced an accumulation of cells in sub-G1 phase, whereas DAC mainly caused an increase of cells in G2/M. Gene expression analysis of AZA- and DAC-treated cells revealed strikingly different profiles, with many genes distinctly regulated by each drug. In summary, while both AZA and DAC caused DNA hypomethylation, distinct effects were demonstrated on regulation of gene expression, cell cycle, DNA damage, and apoptosis.
==========================
上面这段话的重点是AZA作用于G1期,DAC作用于G2/M期。双药联合会有协同作用。
个人公众号:treeofhope
老马  退休老干部 发表于 2012-3-26 21:56:42 | 显示全部楼层
表观基因组修饰
表观遗传学指DNA原始序列没有改变的情况下,对染色质的生化修饰,起到基因调节的作用,特别是对基因表达的调控.这些修饰可以发生在DNA水平(如DNA甲基化),或改变染色质蛋白架构(如组蛋白密码改变).表观基因组涉及的是一群广泛的基因组的开与关,且各个表观遗传学改变不是孤立起作用,是在分子水平上协同作用,影响许多基因的表达.组蛋白密码改变,如乙酰化和去乙酰化较启动子DNA的甲基化更活跃.表观遗传学治疗药物主要有DNA甲基化抑制剂、组蛋白乙酰化抑制剂.理论上,联合使用去甲基化药物和组蛋白去乙酰化酶(HDAC)抑制剂可能更有效.

AZA和5-氮杂-2-脱氧胞苷(5-aza-deoxycytidine,DAC)是通过DNA甲基化酶抑制DNA甲基化.
AZA具有剂量相关的双重效应,高浓度时具有细胞毒作用,低浓度时具有去甲基化作用.
DAC [也称为地西他滨(Decitabine)],高浓度时具有细胞毒作用,低浓度时具有去甲基化作用,抑制DNA甲基化的活性是5-氮杂胞苷的30倍.
AZA与DAC均能引起骨髓抑制.去甲化治疗可能致基因组稳定性丧失而会引发第二肿瘤,但目前临床试验中未能发现去甲化药物致继发性细胞基因学改变和第二肿瘤发生。
个人公众号:treeofhope
老吕  大学三年级 发表于 2016-8-27 17:27:40 | 显示全部楼层
都是高高手

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