4-氨基-1,8-萘二甲酰亚胺：一种新型聚（ADP-核糖）聚合酶抑制剂及辐射增敏剂。
4-Amino-1,8-naphthalimide: a novel inhibitor of poly(ADP-ribose) polymerase and radiation sensitizer.
作者信息
Schlicker A, Peschke P, Bürkle A, Hahn E W, Kim J H
机构信息
Department of Radiation Oncology, German Cancer Research Centre (DKFZ), Heidelberg.
出版信息
Int J Radiat Biol. 1999 Jan;75(1):91-100. doi: 10.1080/095530099140843.
PURPOSE
Poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) is a chromatin-bound enzyme which is known to regulate chromatin structure by poly(ADP-ribosyl)ation of nuclear proteins, to facilitate DNA base excision repair, and to contribute to cellular recovery following DNA damage. Because inhibitors of PARP are able to potentiate the cell-killing effects of some DNA-damaging agents and to inhibit the repair of induced DNA strand breaks, such compounds may enhance the anti-tumour efficacy of radiotherapy or cytotoxic drug treatment. The PARP-inhibitory effects and radiosensitization of a new compound, 4-amino-1,8-naphthalimide (ANI), were examined.
MATERIALS AND METHODS
The inhibition of radiation-induced poly(ADP-ribosyl)ation (50 Gy; 60Co gamma-radiation) was evaluated by immunofluorescence assay using MoAb 10H directed against poly(ADP-ribose). Cell survival was assessed by colony forming assay (CFA) to determine the cytotoxicity of radiosensitization potential in exponentially growing hamster lung fibroblasts (V79), rat prostate carcinoma (R3327-AT1) and human prostate carcinoma (DU145) cells.
RESULTS
At concentrations above 30 nmol x dm(-3) ANI, radiation-induced poly(ADP-ribose) was not detectable by immunofluorescence in V79, AT1 and DU145 cells. At the highest concentration tested for chronic exposure (20 micromol x dm(-3)), ANI was not cytotoxic and significantly potentiates the cytotoxicity of gamma-irradiation. The level of radiation enhancement was directly proportional to drug concentration. Survival curves for the three cell lines using 20 micromol x dm(-3) ANI revealed sensitizer enhancement ratios of 1.3 for V79, 1.5 for AT1 and 1.3 for DU145.
CONCLUSIONS
In living cells, ANI is about 1000-fold more potent at inhibiting PARP activity compared with 3-aminobenzamide (3-ABA). CFA studies demonstrated that ANI is a radiation sensitizer at non-toxic and lower concentrations (20 micromol x dm(-3)) than 3-ABA (10 mmol x dm(-3)).
目的
聚（ADP - 核糖）聚合酶（PARP；EC 2.4.2.30）是一种与染色质结合的酶，已知其通过对核蛋白进行聚（ADP - 核糖基）化来调节染色质结构，促进DNA碱基切除修复，并有助于DNA损伤后的细胞恢复。由于PARP抑制剂能够增强某些DNA损伤剂的细胞杀伤作用，并抑制诱导的DNA链断裂的修复，此类化合物可能会增强放射治疗或细胞毒性药物治疗的抗肿瘤疗效。研究了一种新化合物4 - 氨基 - 1,8 - 萘二甲酰亚胺（ANI）的PARP抑制作用和放射增敏作用。
材料与方法
使用针对聚（ADP - 核糖）的单克隆抗体10H，通过免疫荧光测定法评估辐射诱导的聚（ADP - 核糖基）化（50 Gy；60Coγ射线照射）的抑制情况。通过集落形成测定法（CFA）评估细胞存活率，以确定在指数生长的仓鼠肺成纤维细胞（V79）、大鼠前列腺癌（R3327 - AT1）和人前列腺癌（DU145）细胞中放射增敏潜力的细胞毒性。
结果
在浓度高于30 nmol·dm⁻³时，在V79、AT1和DU145细胞中通过免疫荧光检测不到辐射诱导的聚（ADP - 核糖）。在慢性暴露测试的最高浓度（20 μmol·dm⁻³）下，ANI无细胞毒性，并显著增强γ射线照射的细胞毒性。辐射增强水平与药物浓度成正比。使用20 μmol·dm⁻³ ANI时，三种细胞系的存活曲线显示，V79的增敏剂增强比为1.3，AT1为1.5，DU145为1.3。
结论
在活细胞中，与3 - 氨基苯甲酰胺（3 - ABA）相比，ANI抑制PARP活性的效力约强1000倍。CFA研究表明，ANI在无毒且浓度低于3 - ABA（10 mmol·dm⁻³）的情况下（20 μmol·dm⁻³）是一种放射增敏剂。
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