Hendry J H, Sutton M L
Br J Radiol. 1984 Jun;57(678):507-14. doi: 10.1259/0007-1285-57-678-507.
The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .
使用0.01至1毫克/克体重的单剂量米索硝唑，对处于三种不同氧合状态（影响敏感性）的小鼠尾巴放射性坏死的致敏作用进行了评估。不同注射剂量米索硝唑后的致敏水平可以用最初应用于细胞氧致敏的阿尔珀-霍华德-弗兰德斯关系合理地描述，因此该关系可用于内插法。对于在室温（21-25摄氏度）下用氮气充气夹尾的情况，产生最大致敏作用一半时的注射剂量（定义为K inj）约为0.12-0.17毫克/克体重（0.6-0.8毫摩尔）。在空气中未夹尾的情况下，K inj值约为0.14毫克/克体重，这表明关于致敏作用，氧的背景水平和注射的米索硝唑不是相加的。对于在37摄氏度（接近体核温度）下用氮气充气夹尾的情况，与21-25摄氏度下夹尾相比，敏感性略有增加，注射米索硝唑后敏感性的额外增加（K inj约为0.22毫克/克体重）小于21-25摄氏度时。对于在37摄氏度空气中的尾巴，米索硝唑后敏感性的增加比预期明显得多（K inj约为0.05毫克/克体重）。当使用0.67毫克/克体重的米索硝唑给予八个“每日”分次剂量，且靶细胞在37摄氏度下充分氧合（有效氧增强比约为2.0）时，致敏量小于单剂量，但对于2.6至6.3戈瑞之间的分次辐射剂量，其致敏量相似（即剂量修正）。在剂量为0.1毫克/克体重时，产生的血清水平约相当于人类可耐受的最大值，剂量降低因子仅约为1.03，这大致相当于尾巴坏死率从5%翻倍至10%。随着未来神经毒性较小的药物出现，预计可以耐受更高的血清水平，因此剂量降低因子可能更大。在设计未来使用缺氧细胞放射增敏剂的临床试验时，不应忽视这一适用于小鼠中部分但并非所有测试组织的方面。
