权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Study on the biological properties of nitroimidazole nucleoside analogs as a new hypoxic cell radiosensitizer.

硝基咪唑核苷类似物作为新型缺氧细胞放射增敏剂的生物学特性研究

基本信息

批准号：
01480277
负责人：
MORI Tomoyuki
金额：
$ 2.56万
依托单位：
Tokai University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

A goal for a new hypoxic cell radiosensitizer would be for it to be more effective than, and/or less toxic than, etanidazole (SR2508) or clinically more useful than etanidazole. A potent sensitizer has been synthesized ; this is 2-nitroimidazole nucleoside analog having methoxyglycerol as a sugar moiety at the N-1 position of the imidazole ring (RP-170). Its radiosensitizing activities in vitro and in vivo were investigated and compared with those of etanidazole. As might be expected from the almost identical electron affinities of the two compounds, there were equally effective against hypoxic EMT6 cells in vitro. An intravenous administration (i. v.) of 100mg/kg of RP-170 or the same dose of etanidazole showed an equal sensitizer enhancement ratio (SER) of about 1.4 to solid FMT6 tumor under in vivo-invitro assay and a virtually equal SER of 1.4-1.5 to solid SCCVII tumor under both tumor growth delay assay and TCD50 assay. As predicted from the low partition coefficient, lower drug levels in neural tissue and more rapid serum elimination of RP-170 and etanidazole produced lower acute toxicity than lipophilic sensitizers (e. g. misonidazole). The major advantage of RP-170 over etanidazole is that it has a second route of administration. In contrast to etanidazole, in which the administration route is limited to intravenous injection, with RP170 oral administration also exhibited effective distribution to tumors, sensitizing radiation activity to solid EMT6 and SCCVII tumors. Moreover, LD50 in mice of RP-170 (4.3g/kg on i. v.) was increased to 5.2g/kg by oral administration. This availability of two routes of administration indicates RP-170 as a promising hypoxic cell radiosensitizer for clinical use.

一种新的低氧细胞放射增敏剂的目标是比依坦硝唑(SR2508)更有效和/或毒性更小，或者在临床上比依坦硝唑更有用。合成了一种有效的增敏剂，它是咪唑环N-1位含甲氧基甘油糖基的2-硝基咪唑核苷类似物(RP-170)。考察了其体内外放射增敏活性，并与依坦硝唑进行了比较。正如从两个化合物几乎相同的电子亲和力可以预料到的那样，它们在体外对缺氧的EMT6细胞同样有效。静脉给药(静脉注射)在体外实验中，100 mg/kg的RP-170或相同剂量的依托硝唑对实体瘤FMT6的增敏比(SER)约为1.4，在肿瘤生长延迟实验和TCD50实验中，对实体瘤的增敏比(SER)基本相同，为1.4~1.5。根据低分配系数预测，神经组织中较低的药物浓度和较快的血清消除速度使RP-170和依坦硝唑的急性毒性比亲脂性增敏剂(如咪唑)更低。与依坦硝唑相比，RP-170的主要优势是它有第二条给药途径。与仅限于静脉给药的依坦硝唑不同，RP170口服给药也显示出有效的肿瘤分布，对实体EMT6和SCCVII肿瘤具有增敏作用。此外，RP-170对小鼠的半数致死量(LD50)为4.3g/kg。灌胃给药可达5.2g/kg。这两种给药途径的可用性表明，RP-170是一种有希望的临床使用的低氧细胞放射增敏剂。