Lung Cancer Cell Line Screen Links Fanconi Anemia/BRCA Pathway Defects to Increased Relative Biological Effectiveness of Proton Radiation

相对生物效应 辐射敏感性 克隆形成试验 医学 范科尼贫血 线性能量转移 质子 辐照 癌症研究 癌症 核医学 细胞培养 布拉格峰 放射生物学 DNA修复 放射治疗 DNA 生物 内科学 遗传学 物理 核物理学 量子力学
作者
Qi Liu,Priyanjali Ghosh,Nicole Magpayo,M Testa,Shikui Tang,Liliana Gheorghiu,Peter J. Biggs,Harald Paganetti,Jason A. Efstathiou,Hsiao‐Ming Lu,Kathryn D. Held,Henning Willers
出处
期刊:International Journal of Radiation Oncology Biology Physics [Elsevier BV]
卷期号:91 (5): 1081-1089 被引量:87
标识
DOI:10.1016/j.ijrobp.2014.12.046
摘要

Purpose Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. Methods and Materials For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and 137Cs γ-rays were used. To estimate the RBE of protons relative to 60Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Results Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Conclusions Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation. Growing knowledge of genomic heterogeneity in cancer, especially when it results in altered DNA damage responses, requires re-examination of the generic relative biological effectiveness (RBE) of 1.1 of protons. For determination of cellular radiosensitivity, we irradiated 17 lung cancer cell lines at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer, 2.5 keV/μm). For comparison, 250-kVp X rays and 137Cs γ-rays were used. To estimate the RBE of protons relative to 60Co (Co60eq), we assigned an RBE(Co60Eq) of 1.1 to X rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor damage responses. FANCD2 was depleted using RNA interference. Five lung cancer cell lines (29.4%) exhibited reduced clonogenic survival after proton irradiation compared with X-irradiation with the same physical doses. This was confirmed in a 3-dimensional sphere assay. Corresponding proton RBE(Co60Eq) estimates were statistically significantly different from 1.1 (P≤.05): 1.31 to 1.77 (for a survival fraction of 0.5). In 3 of these lines, increased RBE was correlated with alterations in the Fanconi anemia (FA)/BRCA pathway of DNA repair. In Calu-6 cells, the data pointed toward an FA pathway defect, leading to a previously unreported persistence of proton-induced RAD51 foci. The FA/BRCA-defective cells displayed a 25% increase in the size of subnuclear 53BP1 foci 18 hours after proton irradiation. Our cell line screen has revealed variations in proton RBE that are partly due to FA/BRCA pathway defects, suggesting that the use of a generic RBE for cancers should be revisited. We propose that functional biomarkers, such as size of residual 53BP1 foci, may be used to identify cancers with increased sensitivity to proton radiation.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
Cml发布了新的文献求助30
1秒前
河大谢广坤完成签到,获得积分10
1秒前
2秒前
3秒前
111111发布了新的文献求助10
3秒前
6秒前
陌予发布了新的文献求助10
7秒前
8秒前
缓慢的开山完成签到 ,获得积分10
10秒前
11秒前
量子星尘发布了新的文献求助10
13秒前
ash完成签到,获得积分20
15秒前
15秒前
16秒前
英俊的铭应助月月采纳,获得10
19秒前
ash发布了新的文献求助100
19秒前
周也发布了新的文献求助10
19秒前
文献菜鸟完成签到 ,获得积分10
20秒前
淅淅12345完成签到,获得积分20
20秒前
小二郎应助zhan采纳,获得10
20秒前
23秒前
23秒前
osmanthus完成签到,获得积分10
23秒前
feng1235完成签到,获得积分10
25秒前
拓木幸子完成签到,获得积分10
26秒前
热心市民小红花应助陈昊采纳,获得10
26秒前
27秒前
lcr发布了新的文献求助10
28秒前
Ginkgo完成签到 ,获得积分10
29秒前
安静海露完成签到,获得积分10
29秒前
30秒前
zhan完成签到,获得积分10
31秒前
顾矜应助anna采纳,获得10
31秒前
朴素的士晋完成签到 ,获得积分10
31秒前
33秒前
思源应助YJ888采纳,获得10
33秒前
安静海露发布了新的文献求助10
34秒前
售后延长完成签到 ,获得积分10
35秒前
传奇3应助Cml采纳,获得10
36秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989069
求助须知:如何正确求助?哪些是违规求助? 3531351
关于积分的说明 11253589
捐赠科研通 3269939
什么是DOI,文献DOI怎么找? 1804851
邀请新用户注册赠送积分活动 882074
科研通“疑难数据库(出版商)”最低求助积分说明 809073