MECHANISM BY WHICH CAFFEINE POTENTIATES LETHALITY OF NITROGEN-MUSTARD
MECHANISM BY WHICH CAFFEINE POTENTIATES LETHALITY OF NITROGEN-MUSTARD
复制标题
DOI：
10.1073/pnas.79.9.2942
复制
发表时间：
1982-01-01
期刊：
影响因子：
--
通讯作者：
PARDEE, AB
中科院分区：
文献类型：
--
作者：
LAU, CC;PARDEE, AB
咖啡因与许多dna损伤剂协同作用，增加对哺乳动物细胞的致死率。其机制尚不清楚。咖啡因通过诱导受损细胞在正确修复其DNA损伤之前进行有丝分裂来增强氮芥2-氯- n -（2-氯乙基）- n -甲基乙胺（HN2）的杀伤力。低剂量N2 （0.5 μ）处理。M作用1 h)对幼鼠肾细胞几乎没有致死性（存活率90%）。流式微荧光法和放射自显像显示，这些细胞在用HN2处理后不久就在G2中被捕获。6小时后，hn2处理的细胞开始进入有丝分裂，从此表现得像正常细胞一样。在HN2治疗和放射自显影后，用[3H]胸苷标记的同步细胞脉冲显示修复合成在G2阻滞期间继续进行。咖啡因（2mM）使HN2的致死率提高了5- 10倍。它阻止了G2的逮捕。咖啡因并没有阻止这些经过hn2处理的细胞进入或完成S期，而是允许它们在没有完成修复过程的情况下分裂，结果导致有丝分裂后的核碎裂。如剂量-反应曲线和时间依赖性所示，咖啡因诱导的核碎裂和增强的致死率成正比。低剂量的环己亚胺（一种蛋白质合成抑制剂）可消除致死率和核碎裂。
Caffeine is synergistic with many DNA-damaging agents in increasing lethality to mammalian cells. The mechanism is not well understood. Caffeine potentiates the lethality of the nitrogen mustard 2-chloro-N-(2-chloroethyl)-N-methylethanamine (HN2) by inducing damaged cells to undergo mitosis before properly repairing lesions in their DNA. Treatment with low doses of N2 (0.5 .mu.M for 1 h) caused little lethality in baby hamster kidney cells (90% survival). These cells were arrested in G2 shortly after treatment with HN2 as shown by flow microfluorimetry and autoradiography. After an arrest of 6 h, HN2-treated cells began to move into mitosis and from then on behaved like normal cells. Repair synthesis was shown to continue during the G2 arrest by using synchronized cells pulse labeled with [3H]thymidine after HN2 treatment and autoradiography. Caffeine (2mM) increased the lethality of HN2 by 5- to 10-fold. It prevented the G2 arrest. Caffeine did not prevent these HN2-treated cells from entering or completing S phase but rather allowed them to divide without finishing the repair processes and, as a consequence, caused nuclear fragmentation after mitosis. Caffeine-induced nuclear fragmentation and enhanced lethality were proportional, as shown with dose-response curves and time dependence. Both lethality and nuclear fragmentation were abolished by low doses of cycloheximide, an inhibitor of protein synthesis.