Hirst D G, Hazlehurst J L, Brown J M
Br J Cancer. 1984 Jan;49(1):33-42. doi: 10.1038/bjc.1984.6.
The ability of a range of 2-nitroimidazoles with similar electron affinities but widely differing partition coefficients (P) to enhance the cytotoxicity of cyclophosphamide (CY) in mouse tumour and normal tissues was investigated. In a preliminary study large single doses of benznidazole (BENZ), misonidazole (MISO), desmethylmisonidazole (DMM), and SR-2508 were found to give similar enhancement of the RIF-1 and SCC VII/St tumours. SR-2555 was less effective. A direct comparison was made between MISO and SR-2508 using prolonged, low-level drug exposures, achieved by multiple injections. The enhancement of CY cytotoxicity achieved in the two tumour systems (RIF-1 and SCC VII/St) was found to be similar for a given blood sensitizer concentration. In the normal tissue assays (white blood cell count, bone marrow CFU-S and testis spermatogonia) neither MISO nor SR-2508 produced significant enhancement of CY cytotoxicity, so that the therapeutic gains achieved at a given blood concentration of sensitizer were similar for SR-2508 and MISO. The main advantage of SR-2508, however, will probably lie in its lower toxicity, permitting higher blood levels to be achieved. However, the slope of the dose response curves are rather shallow so we would not predict a dramatically increased benefit.
研究了一系列具有相似电子亲和力但分配系数（P）差异很大的2-硝基咪唑增强环磷酰胺（CY）对小鼠肿瘤组织和正常组织细胞毒性的能力。在一项初步研究中，发现大剂量单次给予苄硝唑（BENZ）、米索硝唑（MISO）、去甲基米索硝唑（DMM）和SR - 2508对RIF - 1和SCC VII/St肿瘤具有相似的增强作用。SR - 2555的效果较差。通过多次注射实现长时间低水平药物暴露，对MISO和SR - 2508进行了直接比较。发现在给定的血敏化剂浓度下，两种肿瘤系统（RIF - 1和SCC VII/St）中CY细胞毒性的增强作用相似。在正常组织检测（白细胞计数、骨髓CFU - S和睾丸精原细胞）中，MISO和SR - 2508均未显著增强CY的细胞毒性，因此在给定血敏化剂浓度下，SR - 2508和MISO实现的治疗增益相似。然而，SR - 2508的主要优势可能在于其较低的毒性，能够达到更高的血药浓度。然而，剂量反应曲线的斜率相当平缓，因此我们预计不会有显著增加的益处。
