EFFECT OF DIMETHYL FUMARATE ON THE RADIATION SENSITIVITY OF MAMMALIAN-CELLS INVITRO
EFFECT OF DIMETHYL FUMARATE ON THE RADIATION SENSITIVITY OF MAMMALIAN-CELLS INVITRO
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DOI：
10.2307/3577299
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发表时间：
1988-09-01
影响因子：
3.4
通讯作者：
BIAGLOW, JE
中科院分区：
文献类型：
--
作者：
HELD, KD;EPP, ER;BIAGLOW, JE
富马酸二甲酯 (DMF) 通过在 GSH-S-转移酶介导的反应中形成共价键来消耗细胞内谷胱甘肽 (GSH)。在中国仓鼠卵巢细胞中，这种消耗很快，例如，室温下 0.5 mM DMF 在 5 分钟内将 GSH 消耗至对照的 10% 以下。 DMF是一种非常有效的缺氧细胞放射增敏剂，细胞在室温下暴露于5 mM DMF 5分钟，其增强比（ER）约为3，且无明显毒性。在相同的药物浓度下，需氧细胞略有增强（ER = 1.3），但缺氧中的 5 mM DMF 导致缺氧剂量反应曲线几乎完全崩溃，达到与含 DMF 的空气中相同的水平。先前有人提出，DMF 通过电子亲和机制使细胞敏化。然而，本研究中的情况似乎并非如此，事实表明，用 DMF 预处理然后洗去药物的细胞与在药物存在下辐照的细胞保持同样的放射敏感性。辐射敏感性的大幅增强似乎与药物消耗硫醇的能力有关，即硫醇似乎是缺氧细胞的放射抗性的主要因素。
Dimethylfumarate (DMF) depletes intracellular glutathione (GSH) by covalent bond formation in a reaction which may be mediated by GSH-S-transferase. In Chinese hamster ovary cells this depletion is rapid, e.g., 0.5 mM DMF depletes GSH to less than 10% of control in 5 min at room temperature. DMF is a very effective hypoxic cell radiosensitizer, with an enhancement ratio (ER) of about 3 obtained by a 5-min exposure of cells at room temperature to 5 mM DMF, without significant toxicity. At this same concentration of drug, there is a small enhancement of aerobic cells (ER = 1.3), but the 5 mM DMF in hypoxia results in nearly a complete collapse of the hypoxic dose-response curve to the same level as seen in air with DMF. It has been suggested previously that DMF sensitizes cells via electron affinic mechanisms. However, this appears not to be the case in this study, as shown by the fact that cells pretreated with DMF and then washed free of the drug remained equally radiosensitive as cells irradiated in the presence of the drug. This large enhancement of radiation sensitivity appears to be related to the drug''s ability to deplete thiols, i.e, thiols appear to be a major factor responsible for radioresistance of hypoxic cells.