Ethacrynic acid: a novel radiation enhancer in human carcinoma cells.
Ethacrynic acid: a novel radiation enhancer in human carcinoma cells.
复制标题
依他尼酸：人类癌细胞中的一种新型辐射增强剂。
DOI：
10.1016/0360-3016(95)02040-3
复制
发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Kim,JH
中科院分区：
文献类型：
--
作者：
Khil,MS;Kim,SH;Pinto,JT;Kim,JH
目的：由于干扰硫醇代谢和谷胱甘肽 S-转移酶 (GST) 功能的药物已被证明可以在体外和体内增强烷化剂的抗肿瘤作用，因此本研究的构想是基于 GST 抑制剂会增强某些选定人类癌细胞的放射反应。选择依他尼酸 (EA) 进行研究是因为它是一种有效的 GST 抑制剂，也是一种众所周知的人体利尿剂。 方法和材料：实验采用在 Eagle 最低必需培养基 (MEM) 中生长且补充有 10% 胎牛血清 (FCS) 的成熟人类肿瘤细胞进行。使用的细胞系是MCF-7、MCF-7阿霉素耐药(AR)细胞(乳腺癌)、HT-29细胞(结肠癌)、DU-145细胞(前列腺癌)和U-373细胞(恶性神经胶质瘤)。通过确定培养物中单铺板细胞的集落形成能力来测定细胞暴露于单独药物、单独放射和联合治疗后的细胞存活以获得剂量-存活曲线。药物增强率与GST水平相关。结果：与MCF-7 AR和HT-29细胞相比，EA的细胞毒性在MCF-7、U-373和DU-145细胞中最明显。发现 EA 敏感细胞中 GST 活性水平较低。在辐射之前或之后立即将 EA 敏感细胞暴露于无毒浓度的药物中，可以获得显着的辐射增强。 EA (20μl)对MCF-7细胞的增敏剂增强比(SER)为1.55，而MCF-7 AR的SER小于1.1。基于五种不同的人类肿瘤细胞，在联合治疗前，肿瘤细胞的SER和GST水平之间存在明显的负相关关系。结论：本研究结果表明，EA作为GST活性的可逆和不可逆抑制剂，可以显着增强人类癌细胞的放射反应，肿瘤细胞中GST的水平可以预测EA的放射增强程度。依他尼酸将是一种极好的药物，作为进一步体内肿瘤研究的放射增敏剂。
Purpose: Because agents that interfere with thiol metabolism and glutathione S-transferase (GST) functions have been shown to enhance antitumor effects of alkylating agents in vitro and in vivo, the present study was conceived on the basis that an inhibitor of GST would enhance the radiation response of some selected human carcinoma cells. Ethacrynic acid (EA) was chosen for the study because it is an effective inhibitor of GST and is a well known diuretic in humans.Methods and Materials: Experiments were carried out with well-established human tumor cells in culture growing in Eagle’s minimum essential medium (MEM) supplemented with 10% fetal calf serum (FCS). Cell lines used were MCF-7, MCF-7 adriamycin resistant (AR) cells (breast carcinoma), HT-29 cells (colon carcinoma), DU-145 cells (prostate carcinoma), and U-373 cells (malignant glioma). Cell survival following the exposure of cells to drug alone, radiation alone, and a combined treatment was assayed by determining the colony-forming ability of single plated cells in culture to obtain dose-survival curves. The drug enhancement ratio was correlated with levels of GST.Results: The cytotoxicity of EA was most pronounced in MCF-7, U-373, and DU-145 cells compared to MCF-7 AR and HT-29 cells. The levels of GST activity were found to be lower in those EA-sensitive cells. A significant radiation enhancement was obtained with EA-sensitive cells exposed to nontoxic concentrations of the drug immediately before or after irradiation. The sensitizer enhancement ratio (SER) of MCF-7 cells was 1.55 with EA (20 &ml), while the SER of MCF-7 AR was less than 1.1. Based on five different human tumor cells, a clear inverse relationship was demonstrated between the magnitude of SER and GST levels of tumor cells prior to the combined treatment.Conclusion: The present results suggest that EA, which acts as both a reversible and irreversible inhibitor of GST activity, could significantly enhance the radiation response of human cancer cells and the level of GST in tumor cells may predict the magnitude of radiation enhancement with EA. Ethacrynic acid would be an excellent drug as a radiosensitizer for further in vivo tumor study.