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药物的耐受性和耐药性

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26845 44 老马 发表于 2013-8-4 20:36:14 |
老马  博士一年级 发表于 2013-8-5 01:40:53 | 显示全部楼层 来自: 浙江温州
Evolution of resistance to anti-cancer therapy during general dosing schedules.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826560/
Evolution of resistance to anti-cancer therapy during general dosing schedules.pdf (1.82 MB, 下载次数: 58)

The Dynamics of Drug Resistance: A Mathematical Perspective
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348255/
The Dynamics of Drug Resistance A Mathematical Perspective.pdf (684.52 KB, 下载次数: 44)

Effects of Pharmacokinetic Processes and Varied Dosing Schedules on the Dynamics of Acquired Resistance to Erlotinib in EGFR-Mutant Lung Cancer
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693219/
Effects of Pharmacokinetic Processes and Varied Dosing Schedules.pdf (1.86 MB, 下载次数: 40)

Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer Modeling
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500629/

The effect of one additional driver mutation on tumor progression
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567469/

The effect of one additional driver mutation on tumor progression.pdf

1.12 MB, 下载次数: 57

个人公众号:treeofhope
老马  博士一年级 发表于 2013-8-5 01:42:43 | 显示全部楼层 来自: 浙江温州
Alternative Dosing Schedule Could Delay Resistance to Targeted Melanoma Therapy
http://wwwtest.cancercommons.org ... d-melanoma-therapy/
Treatment with vemurafenib, a drug in the BRAF inhibitor family, results in rapid tumor shrinkage in metastatic melanoma patients with the V600E BRAF mutation. The response lasts for months, but unfortunately, tumors ultimately become resistant to the treatment. Currently, vemurafenib is given as an oral dose on a daily basis. But a new study published in Nature (doi:10.1038/nature11814) suggests that a 4-weeks-on, 2-weeks-off dosing schedule may help to stave off resistance.

The study was performed in a mouse model of metastatic melanoma by Darrin Stuart, a senior investigator at the Novartis Institutes for Biomedical Research in California and Martin McMahon, a professor of cancer biology at the Helen Diller Family Comprehensive Cancer Center at the University of California in San Francisco. These investigators and colleagues used mice that had received xenografts (transplants of human tissue) of BRAF-mutated melanoma. The researchers created vemurafenib-resistant tumors in these mice by giving them a daily, continuous dose of vemurafenib.

Culturing of vemurafenib-resistant tumor cells taken from the mouse models led to an interesting observation. The resistant cells had difficulty growing unless the media was spiked with vemurafenib. “The fitness benefit given to resistant cells by elevated BRAF (V600E) in the presence of vemurafenib becomes a fitness deficit when the drug is removed,” state the authors in the paper.

McMahon and colleagues then compared a continuous vemurafenib treatment schedule with a 4-weeks-on, 2-weeks-off schedule in the BRAF-mutant mouse model. While the mice that were continuously dosed developed vemurafenib-resistant melanoma within 100 days of starting the treatment, mice given vemurafenib on an on-off schedule did not have drug-resistant melanoma as many as 200 days after their initial therapy.

These results suggest that constant exposure to vemurafenib leads to resistance and that an intermittent dosing schedule could delay—if not prevent—resistance. Whether the same results will be observed in patients needs to be tested. The perfect dosing schedule would balance between allowing tumors to regress and stalling resistance

More basic research in mouse models is needed, but the concept could be tested in a metastatic melanoma clinical trial soon. This study also has implications for other targeted therapies. Hopefully, testing various dosing schedules of targeted agents to find an optimal balance between response and rate of resistance will now be a high priority for not just melanoma researchers, but for all cancer researchers. For example, it is possible that continuous dosing contributes to the rate of resistance to other targeted agents, such as imatinib (Gleevec) prescribed for chronic myeloid leukemia. This could be relatively easily tested in experimental models and then in clinical trials.
个人公众号:treeofhope
老马  博士一年级 发表于 2013-8-5 02:07:05 | 显示全部楼层 来自: 浙江温州
请等待,我将在一周内翻译以上文档。
个人公众号:treeofhope
大灰狼  高中三年级 发表于 2013-8-5 08:26:37 | 显示全部楼层 来自: 陕西咸阳
马哥威武!
定江定海  大学三年级 发表于 2013-8-5 08:45:24 | 显示全部楼层 来自: 广东深圳
吃8 停5有实验数据支撑了?
qingyang  高中一年级 发表于 2013-8-5 08:57:25 | 显示全部楼层 来自: 广东深圳
马哥,愿意为你承担翻译一些文档。
不过我从来没翻译过医学文档,希望能从简单的开始。
定江定海  大学三年级 发表于 2013-8-5 09:15:11 | 显示全部楼层 来自: 广东深圳
强烈支持, 第一句是翻译成 “轮换给药方式可以延迟黑色素瘤靶向治疗的耐药” 还是“非正统给药方式可以延迟黑色素瘤靶向治疗的耐药”
感受生活  高中一年级 发表于 2013-8-5 09:58:01 | 显示全部楼层 来自: 山东青岛
老马!的确威武!
老马  博士一年级 发表于 2013-8-5 16:32:20 | 显示全部楼层 来自: 浙江温州
易瑞沙、特罗凯的剂量方案问题
(1)易瑞沙的临床试验结果显示,500mg每天与250mg每天的平均耐药时间相近,而500mg每天的副作用更大。
(2)对于正在抽烟的肺癌病人,需要300mg每天才能达到不抽烟病人服用150mg每天的效果,但抽烟病人的平均耐药时间要短的多。
(3)对于无法耐受特罗凯150mg每天标准剂量的病人,可以采用:
150mg第1天/100mg第2天的隔天方案;100mg每天,50mg每天,甚至25mg每天。
以取得副作用与正作用的平衡。对耐药时间无影响 。
(4)漏服特罗凯会加快耐药,比如第1-5天服特罗凯,第6-7天漏服。
(5)Bibw 2992(PF00299804的情况类似)在体外实验中,肿瘤细胞在清洗Bibw2992后,72小时内仍然受到抑制。因此Bibw2992和PF00299804这二个不可逆药物可以采用吃8天停2天方案,有二个好处:1是减轻副作用,影响正作用不大;2是减缓耐药的出现。
(6)对付脑转病人(特罗凯耐药)的特罗凯脉冲方案(每周900-1500mg,即6片到10片):目前有第1天吃4片(600mg)特罗凯,接着停3天特罗凯;第1天吃10片(1500mg)特罗凯,接着停6天特罗凯;第1天和第2天各吃5片(各750mg)特罗凯,接着停5天特罗凯;第1天吃10片(1500mg)特罗凯,接着吃6天50mg特罗凯。最后一种方案效果最好。
(7)目前不推荐EGFR类靶向药同天混用,会加大副作用,正作用未知。
(8)对于19突变/T790突变的肺癌细胞,经过35-40天空窗期,87.5%的T790突变肿瘤细胞会减少到1%;而对于21突变/T790突变的肺癌细胞,不会恢复对特罗凯的敏感性。
个人公众号:treeofhope

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一步错步步错  大学二年级 发表于 2013-8-5 17:43:26 | 显示全部楼层 来自: 四川
看来21突变在治疗上不如19突变的办法多啊。

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