Relationship Between Chromatin Structure and Sensitivity to Molecularly Targeted Auger Electron Radiation Therapy

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• 作者：Samantha Y.A. Terry ; Ph.D. ; Katherine A. Vallis ; Ph.D. ; ^{katherine.vallis@oncology.ox.ac.uk}
• 关键词：Radiosensitivity ; Auger electrons ; Chromatin structure ; Suberoylanilide hydroxamic acid
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2012
• 期刊代码：136_03603016
• 类别：med
• 出版时间：15 July, 2012
• 卷：83
• 期：4
• 页码：1298-1305
• 文件大小：781 K

摘要

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Purpose

The open structure of euchromatin renders it susceptible to DNA damage by ionizing radiation (IR) compared with compact heterochromatin. The effect of chromatin configuration on the efficacy of Auger electron radiotherapy was investigated.

Methods and Materials

Chromatin structure was altered in MDA-MB-468 and 231-H2N human breast cancer cells by suberoylanilide hydroxamic acid (SAHA), 5-aza-2-deoxycytidine, or hypertonic treatment. The extent and duration of chromatin structural changes were evaluated using the micrococcal nuclease assay. DNA damage (纬H2AX assay) and clonogenic survival were evaluated after exposure to ¹¹¹In-DTPA-hEGF, an Auger electron-emitting radiopharmaceutical, or IR. The intracellular distribution of ¹¹¹In-DTPA-hEGF after chromatin modification was investigated in cell fractionation experiments.

Results

Chromatin remained condensed for up to 20 minutes after NaCl and in a relaxed state 24 hours after SAHA treatment. The number of 纬H2AX foci per cell was greater in MDA-MB-468 and 231-H2N cells after IR (0.5 Gy) plus SAHA (1 渭M) compared with IR alone (16 卤 0.6 and 14 卤 0.3 vs. 12 卤 0.4 and 11 卤 0.2, respectively). More 纬H2AX foci were observed in MDA-MB-468 and 231-H2N cells exposed to ¹¹¹In-DTPA-hEGF (6 MBq/渭g) plus SAHA vs. ¹¹¹In-DTPA-hEGF alone (11 卤 0.3 and 12 卤 0.7 vs. 9 卤 0.4 and 7 卤 0.3, respectively). 5-aza-2-deoxycytidine enhanced the DNA damage caused by IR and ¹¹¹In-DTPA-hEGF. Clonogenic survival was reduced in MDA-MB-468 and 231-H2N cells after IR (6 Gy) plus SAHA (1 渭M) vs. IR alone (0.6%卤 0.01 and 0.3%卤 0.2 vs. 5.8%卤 0.2 and 2%卤 0.1, respectively) and after ¹¹¹In-DTPA-hEGF plus SAHA compared to ¹¹¹In-DTPA-hEGF alone (21%卤 0.4%and 19%卤 4.6 vs. 33%卤 2.3 and 32%卤 3.7). SAHA did not affect ¹¹¹In-DTPA-hEGF nuclear localization. Hypertonic treatment resulted in fewer 纬H2AX foci per cell after IR and ¹¹¹In-DTPA-hEGF compared to controls but did not significantly alter clonogenic survival.

Conclusions

Chromatin structure affects DNA damage and cell survival after exposure to Auger electron radiation.