Held K D, Epp E R, Awad S, Biaglow J E
Department of Radiation Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Radiat Res. 1991 Jul;127(1):75-80.
Dimethyl fumarate (DMF) depletes intracellular glutathione (GSH) by covalent bond formation in a reaction mediated by GSH-S-transferase. Treatment of hypoxic Chinese hamster V79 cells with 5 mM DMF before irradiation radiosensitizes the cells, resulting in an enhancement ratio (ER) of about 2.7 with minimal toxicity, when the end point is clonogenic cell survival. Under the same conditions aerobic cells are sensitized, and ER of about 1.3 is found, and GSH is reduced to about 3% of control. Very similar results were obtained previously with Chinese hamster ovary (CHO) cells. In addition, new data presented here show that DMF treatment of V79 or CHO cells immediately after irradiation under hypoxic conditions sensitizes the cells, resulting in an ER of about 1.5, DMF treatment after irradiation under aerobic conditions results in an ER of 1.3, and this DMF treatment reduces protein thiols (PSH) to about 70% of control. When induction of DNA damage is measured using the neutral elution assay, treatment of V79 or CHO cells with DMF prior to irradiation under hypoxic conditions results in an ER of 1.9-2.0, but there is no enhancement of DNA damage when DMF is added after irradiation under hypoxic conditions or when cells are treated with DMF before or after irradiation under aerobic conditions. Based on these data we postulate that DMF radiosensitizes killing of hypoxic cells by two actions: depletion of GSH interferes with the chemical competition between damage fixation and repair, and depletion of PSH causes an inhibition of enzymatic repair processes. We also suggest that DMF sensitizes aerobic cells only by inhibition of enzymatic repair processes.
富马酸二甲酯（DMF）在谷胱甘肽-S-转移酶介导的反应中通过共价键形成消耗细胞内谷胱甘肽（GSH）。在照射前用5 mM DMF处理缺氧的中国仓鼠V79细胞会使细胞对辐射敏感，当终点为克隆形成细胞存活时，毒性最小，增强比（ER）约为2.7。在相同条件下，需氧细胞也会被致敏，ER约为1.3，GSH降低至对照的约3%。此前用中国仓鼠卵巢（CHO）细胞也获得了非常相似的结果。此外，此处给出的新数据表明，在缺氧条件下照射后立即用DMF处理V79或CHO细胞会使细胞致敏，ER约为1.5，在需氧条件下照射后用DMF处理ER为1.3，这种DMF处理会使蛋白质巯基（PSH）降低至对照的约70%。当使用中性洗脱测定法测量DNA损伤的诱导时，在缺氧条件下照射前用DMF处理V79或CHO细胞，ER为1.9 - 2.0，但在缺氧条件下照射后添加DMF或在需氧条件下照射前或后用DMF处理细胞时，DNA损伤没有增强。基于这些数据，我们推测DMF通过两种作用使缺氧细胞的杀伤对辐射敏感：GSH的消耗干扰了损伤固定和修复之间的化学竞争，PSH的消耗导致酶促修复过程受到抑制。我们还认为DMF仅通过抑制酶促修复过程使需氧细胞致敏。
