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

新的低氧细胞放射增敏剂的目标是使其比依他硝唑（SR 2508）更有效和/或毒性更小，或者比依他硝唑在临床上更有用。已经合成了一种有效的敏化剂;这是在咪唑环的N-1位具有甲氧基甘油作为糖部分的2-硝基咪唑核苷类似物（RP-170）。研究了它的体内外放射增敏作用，并与依他硝唑进行了比较。正如从两种化合物几乎相同的电子亲和力所预期的，在体外对缺氧EMT 6细胞同样有效。静脉内施用（i.（五）RP-170 100 mg/kg或相同剂量的依他硝唑对FMT 6实体瘤的增敏比（SER）约为1.4，对SCCVII实体瘤的增敏比（SER）在肿瘤生长延迟试验和TCD 50试验中均为1.4-1.5。正如从低分配系数预测的那样，神经组织中较低的药物水平和RP-170和依他硝唑更快的血清消除产生的急性毒性低于亲脂性致敏剂（例如，G.米索硝唑）。RP-170相对于依他硝唑的主要优势在于它具有第二种给药途径。与给药途径限于静脉内注射的依他硝唑相反，RP 170口服给药也表现出有效的肿瘤分布，使放射活性对实体EMT 6和SCCVII肿瘤增敏。RP-170（4.3g/kg，i.（五）经口给药后，剂量增加至5.2g/kg。两种给药途径的可用性表明RP-170是一种有前景的临床应用乏氧细胞放射增敏剂。

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.