Murayama C, Suzuki A, Sato C, Tanabe Y, Shoji T, Miyata Y, Nishio A, Suzuki T, Sakaguchi M, Mori T
Department of Radiation Oncology, School of Medicine, Tokai University, Isehara, Japan.
Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):433-43. doi: 10.1016/0360-3016(93)90961-t.
A new hypoxic cell sensitizer has been synthesized; this is a 2-nitroimidazole nucleoside analog having erythritol as a sugar moiety at the N-1 position of the imidazole ring (RP-343). Its possibility as a potent hypoxic cell sensitizer was compared with those of RP-170 and etanidazole.
Radiosensitization was tested in two murine tumors, EMT6 using in vitro and in vivo-in vitro assays and SCCVII using growth delay and TCD50 assays. Pharmacokinetic study was performed in Balb/c mice bearing EMT6 tumors and in Beagle dogs. LD50 of each sensitizer was obtained with ICR mice.
As might be expected from the almost identical electron affinities of the three sensitizers, they were equally effective against hypoxic EMT6 cells in vitro. While having the lowest partition coefficient (0.035), RP-343 exhibited almost equally effective distribution to tumors and sensitizing radiation activity. An intravenous (i.v.) injection of 100 mg/kg of RP-343, RP-170 and etanidazole showed an almost equal sensitizer enhancement ratio (SER) of about 1.4 to solid EMT6 tumor under in vivo-in vitro assay and a virtually equal SER of 1.33-1.44 to solid SCCVII tumor under both tumor growth delay assay and TCD50 assay. A great advantage of RP-343 over RP-170 and etanidazole is its very much lower toxicity; their LD50 in mice were > 6.0, 4.3 and 4.8 g/kg, respectively, on i.v. injection. The lower toxicity of RP-343 was supported by its lower concentrations in the brain; the RP-343 AUC for brain was 0.43 times that of RP-170. Three indices were selected to compare the three nitroimidazoles. SER at 5% LD50 doses of RP-343, RP-170 and etanidazole was 1.66, 1.59 and 1.56. At the same toxicity levels, RP-343 was found to have better sensitization of solid tumors over both etanidazole and RP-170. The maximum tumor concentration/AUC for brain (Cmax,tumor/AUCbrain) ratios for RP-343 and RP-170 were 9.62 and 3.98.
This extremely high ratio of RP-343 could explain its lower toxicity than RP-170 or etanidazole. The therapeutic risk index defined as D1.5/LD50 (D1.5 is the sensitizer dose to obtain the SER of 1.5 in vivo) for RP-343, RP-170 and etanidazole were 0.022, 0.033 and 0.036, respectively. Especially, the effectively lower therapeutic risk index for RP-343 presents the possibility of clinical advantage over etanidazole.
合成了一种新的低氧细胞增敏剂；这是一种2-硝基咪唑核苷类似物，在咪唑环的N-1位具有赤藓糖醇作为糖部分（RP-343）。将其作为强效低氧细胞增敏剂的可能性与RP-170和依他硝唑进行了比较。
在两种小鼠肿瘤中测试放射增敏作用，对EMT6肿瘤采用体外和体内-体外试验，对SCCVII肿瘤采用生长延迟和TCD50试验。在荷EMT6肿瘤的Balb/c小鼠和比格犬中进行药代动力学研究。用ICR小鼠获得每种增敏剂的半数致死量（LD50）。
正如从三种增敏剂几乎相同的电子亲和力所预期的那样，它们在体外对低氧EMT6细胞同样有效。虽然RP-343的分配系数最低（0.035），但其在肿瘤中的分布和增敏辐射活性几乎同样有效。在体内-体外试验中，静脉注射100mg/kg的RP- 343、RP-170和依他硝唑对实体EMT6肿瘤的增敏剂增强比（SER）几乎相等，约为1.4；在肿瘤生长延迟试验和TCD50试验中，对实体SCCVII肿瘤的SER实际上相等，为1.33 - 1. 44。RP-343相对于RP-170和依他硝唑的一个很大优势是其毒性非常低；静脉注射时，它们在小鼠中的LD50分别>6.0、4.3和4.8g/kg。RP-343在脑中的浓度较低，这支持了其较低的毒性；RP-343在脑中的药时曲线下面积（AUC）是RP-170的0.43倍。选择三个指标来比较这三种硝基咪唑。RP-343、RP-170和依他硝唑在5%LD50剂量下的SER分别为1.66、1.59和1.56。在相同毒性水平下，发现RP-343对实体肿瘤的增敏作用优于依他硝唑和RP-170。RP-343和RP-170的最大肿瘤浓度/脑AUC（Cmax,tumor/AUCbrain）比值分别为9.62和3.98。
RP-343的这一极高比值可以解释其毒性低于RP-170或依他硝唑。RP-343、RP-170和依他硝唑的治疗风险指数定义为D1.5/LD50（D1.5是在体内获得SER为1.5的增敏剂剂量），分别为0.022、0.033和0.036。特别是，RP-343有效较低的治疗风险指数显示出相对于依他硝唑在临床上具有优势的可能性。
