Sensitization of normal and malignant tissue to cyclophosphamide by nitroimidazoles with different partition coefficients.
Sensitization of normal and malignant tissue to cyclophosphamide by nitroimidazoles with different partition coefficients.
复制标题
不同分配系数的硝基咪唑对正常和恶性组织对环磷酰胺的敏感性。
DOI：
10.1038/bjc.1984.6
复制
发表时间：
1984
影响因子：
8.8
通讯作者：
Brown,JM
中科院分区：
文献类型：
--
作者：
Hirst,DG;Hazlehurst,JL;Brown,JM
研究了一系列电子亲和力相近但分配系数(P)相差很大的2-硝基咪唑对环磷酰胺(CY)在小鼠肿瘤和正常组织中的细胞毒性的增强作用。在一项初步研究中，发现大剂量单次大剂量苯硝唑(Benz)、米索(MISO)、去甲基咪唑(DMM)和SR-2508对RIF-1和SCC VII/ST肿瘤有类似的增强作用。SR-2555的药效较差。在MISO和SR-2508之间进行了直接比较，使用通过多次注射实现的长期、低水平药物暴露。在两种肿瘤系统(RIF-1和SCC VII/ST)中，在给定的血液增敏剂浓度下，CY细胞毒性的增强被发现是相似的。在正常组织检测(白细胞计数、骨髓巨噬细胞集落形成单位S和睾丸精原细胞)中，MISO和SR-2508都不能显著增强CY的细胞毒作用，因此，在给定的增敏剂血药浓度下，SR-2508和MISO的治疗效果相似。然而，SR-2508的主要优势可能在于其较低的毒性，允许实现更高的血液水平。然而，剂量反应曲线的斜率相当浅，因此我们不会预测收益会大幅增加。
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.