The chemopreventive agent oltipraz stimulates repair of damaged DNA.
The chemopreventive agent oltipraz stimulates repair of damaged DNA.
复制标题
化学预防剂吡噻硫酮可刺激受损 DNA 的修复。
作者：
P. O'dwyer;S. Johnson;C. Khater;A. Krueger;Y. Matsumoto;T. C. Hamilton;K. Yao
致癌物可以通过产生导致原位碱基修饰的自由基或通过在相对亲核位点形成大体积加合物来破坏DNA。临床前研究已经证明，施用二硫杂环戊硫酮奥替普拉可保护实验室动物在随后暴露于多种致癌物后免于发生肿瘤。这可能是通过诱导解毒基因表达的机制发生的。在某些模型中，致癌物暴露后的奥替普拉治疗也可能提供保护。为了研究这一观察结果的可能机制，我们研究了奥替普拉对碱基切除修复和铂-DNA损伤形成和清除的影响。通过测量未处理和奥替普拉处理的HT-29全细胞提取物对脱嘌呤/脱嘧啶位点的修复的体外测定，未观察到奥替普拉对碱基切除修复的影响。在不存在或存在30和100 μ M奥替普拉的情况下用顺铂处理HT-29细胞减少了铂在DNA中的积累。在用顺铂和增加浓度的奥替普拉同时处理的纯化DNA中也观察到DNA铂化的剂量依赖性减少。当DNA首先铂化，随后孵育与oltipraz，没有减少铂含量在DNA中被发现。HT-29细胞与oltipraz预孵育提高总铂-DNA加合物和链间交联的去除率。这些数据支持了一种新的机制，通过这种机制，二硫代硫酮可以保护暴露于致癌物的动物免受肿瘤形成的影响，并可能扩大其在临床中的潜在作用。
Carcinogens may damage DNA either through the production of radicals that cause base modification in situ or through the formation of bulky adducts at relatively nucleophilic sites. Preclinical studies have demonstrated that administration of the dithiolethione oltipraz protects laboratory animals from the development of tumors following subsequent exposure to a variety of carcinogens. This may occur through a mechanism involving the induction of detoxicating gene expression. In some models, oltipraz treatment following carcinogen exposure may also confer protection. To investigate a possible mechanism for this observation, we studied the effects of oltipraz on base excision repair and platinum-DNA damage formation and removal. No effect of oltipraz was observed on base excision repair as determined by an in vitro assay measuring the repair of apurinic/apyrimidinic sites by untreated and oltipraz-treated HT-29 whole-cell extracts. Treatment of HT-29 cells with cisplatin in the absence or presence of 30 and 100 microM oltipraz decreased the accumulation of platinum in DNA. A dose-dependent reduction in DNA platination was also observed in purified DNA treated concurrently with cisplatin and increasing concentrations of oltipraz. When DNA was first platinated and subsequently incubated with oltipraz, no decrease in platinum content in DNA was found. Preincubation of HT-29 cells with oltipraz enhanced the rate of removal of total platinum-DNA adducts and interstrand cross-links. These data support a novel mechanism through which dithiolethiones may protect carcinogen-exposed animals from tumor formation and may expand their potential role in the clinic.
登录
查看更多内容
大鼠肝脏中化学保护剂 5-(2-吡嗪基)-4-甲基-1,2-二硫醇-3-硫酮 (oltipraz) 对谷胱甘肽 S-转移酶基因表达的转录控制。
影响因子：
11.2
作者：
Davidson,NE;Egner,PA;Kensler,TW
通讯作者：
Kensler,TW
爪蟾卵母细胞增殖细胞核抗原依赖性脱碱基位点修复：碱基切除 DNA 修复的替代途径。
影响因子：
5.3
作者：
Matsumoto,Y;Kim,K;Bogenhagen,DF
通讯作者：
Bogenhagen,DF
饲喂 5-(2-吡嗪基)-4-甲基-1,2-二硫醇-3-硫酮（吡噻硫酮）及相关 1,2-二硫醇-3-硫酮和 1,2-二硫醇的大鼠抗黄曲霉毒素致瘤性的机制
影响因子：
11.2
作者：
Kensler,TW;Egner,PA;Dolan,PM;Groopman,JD;Roebuck,BD
通讯作者：
Roebuck,BD
膳食奥替普拉对雄性 F344 大鼠中氧化偶氮甲烷诱导的实验性肠道癌的抑制作用。
影响因子：
4.7
作者：
Rao,CV;Tokomo,K;Kelloff,G;Reddy,BS
通讯作者：
Reddy,BS
中国仓鼠卵巢细胞中顺铂链内加合物和链间交联的基因特异性形成和修复。
DOI：
--
发表时间：
1991
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jones,JC;Zhen,WP;Reed,E;Parker,RJ;Sancar,A;Bohr,VA
通讯作者：
Bohr,VA