Williams M V, Denekamp J, Minchinton A I, Stratford M R
Br J Cancer. 1982 Jul;46(1):127-37. doi: 10.1038/bjc.1982.174.
The radiosensitizing efficiencies of 4 structural analogues of misonidazole (MISO) have been compared with that of the parent compound. Three of these were charged basic compounds, previously shown in vitro to be 10 times more efficient. Enhancement ratios were measured from pairs of tumour growth-delay curves for the mouse fibrosarcoma SA Fab. Two routes of administration and ranges of drug dose and intervals between injection and irradiation were tested. Drug concentrations in blood, brain and tumor were measured using high-performance liquid chromatography. The peak concentration in tumours coincided with the peak in radiosensitization: 20 min after i.v. injection and 40 min after i.p. injection. The concentration in tumours was similar for either route. Comparison of radiosensitizing efficiency on the basic of equal administered dose showed no difference between the 5 compounds, but after equimolar doses the charged compounds achieved lower tumour concentrations. Comparison of sensitizing efficiency on the basis of tumour concentration showed that they were 3 times more potent than MISO, as predicted from their higher electron-affinity. The resultant improvement in radiosensitization at low, clinically relevant, concentrations is so slight that any therapeutic benefit would depend on reduced drug toxicity in man.
已将米索硝唑（MISO）的4种结构类似物的放射增敏效率与母体化合物的放射增敏效率进行了比较。其中三种是带电荷的碱性化合物，先前在体外实验中显示其效率要高10倍。通过小鼠纤维肉瘤SA Fab的成对肿瘤生长延迟曲线来测量增强比。测试了两种给药途径以及药物剂量范围和注射与照射之间的间隔时间。使用高效液相色谱法测量血液、脑和肿瘤中的药物浓度。肿瘤中的峰值浓度与放射增敏的峰值一致：静脉注射后20分钟和腹腔注射后40分钟。两种途径在肿瘤中的浓度相似。基于相等给药剂量比较放射增敏效率，这5种化合物之间没有差异，但在等摩尔剂量后，带电荷的化合物在肿瘤中的浓度较低。基于肿瘤浓度比较增敏效率表明，正如根据其较高的电子亲和力所预测的那样，它们的效力是MISO的3倍。在低的、临床相关浓度下放射增敏的最终改善非常轻微，以至于任何治疗益处都将取决于降低人体中的药物毒性。
