Post-irradiation sensitization with the ADP-ribosyltransferase inhibitor 3-acetamidobenzamide.
Post-irradiation sensitization with the ADP-ribosyltransferase inhibitor 3-acetamidobenzamide.
复制标题
使用 ADP-核糖基转移酶抑制剂 3-乙酰氨基苯甲酰胺进行辐射后致敏。
DOI：
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发表时间：
1984
期刊：
影响因子：
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通讯作者：
B. Hunt
中科院分区：
文献类型：
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作者：
J. Lunec;A. George;M. Hedges;W. Cramp;W. Whish;B. Hunt
近年来，一些证据表明，核ADP-核糖基转移酶（ADPRT）的活性参与DNA修复，虽然只有在某些情况下，ADPRT活性的细胞存活的要求已被证明。我们进一步研究了ADP-核糖基化在细胞对电离辐射的反应中可能发挥的作用，使用3-乙酰氨基苯甲酰胺（3-AAB），一种高效的ADPRT抑制剂。使用该化合物，我们已经证明，如果在照射后修复期间使用对未照射细胞无毒的浓度的3-AAB将ADP-核糖基化抑制到足够的程度，则观察到细胞杀伤的显著增强。抑制剂是有效的关键时期内的第一个90分钟照射后，和可恢复的辐射损伤的半衰期估计为约20分钟。治疗与3-AAB减缓DNA链断裂修复的速度，但没有阻止最终修复的断裂，用于确定DNA链断裂的碱性解旋方法的分辨率范围内。虽然大多数断裂最终修复，辐射诱导的姐妹染色单体交换和染色体畸变的频率增加，表明发生了更多的基因组重排，可能是由于ADPRT活性被抑制时，在辐射后修复期间的持久性断裂。这表明，增加频率的转座和重组，这些观察结果反映可能与增加的致命突变的风险，一些可能涉及染色体畸变。
In recent years several lines of evidence have indicated that nuclear ADP-ribosyltransferase (ADPRT) activity is involved in DNA repair, although the requirement of ADPRT activity for cell survival has only been demonstrated in certain cases. We have investigated further the possible role of ADP-ribosylation in the response of cells to ionizing radiation, using 3-acetamidobenzamide (3-AAB), a highly effective inhibitor of ADPRT. With this compound we have demonstrated that marked enhancement of cell killing is observed if ADP-ribosylation is inhibited to a sufficient extent during the post-irradiation repair period, using concentrations of 3-AAB which are not toxic towards unirradiated cells. The critical period within which the inhibitor was effective was the first 90 min post-irradiation, and the half life of the recoverable radiation damage involved was estimated as approximately 20 min. Treatment with 3-AAB slowed the rate at which DNA strand breaks were repaired but did not prevent the ultimate repair of breaks, within the limits of resolution of the alkaline unwinding method used to determine DNA strand breakage. Although the majority of breaks were ultimately repaired, the frequency of radiation-induced sister chromatid exchanges and chromosome aberrations was increased, indicating that more genomic rearrangement had taken place, possibly as a consequence of the persistence of breaks when ADPRT activity was inhibited by 3-AAB during the post-irradiation repair period. It is suggested that the increased frequency of transposition and recombination which these observations reflect is likely to be associated with an increased risk of lethal mutations, some possibly involving chromosomal aberrations.