Raleigh J A, Shum F Y, Koziol D R, Saunders W M
Cancer Clin Trials. 1980 Spring;3(1):55-62.
Normal tissue toxicity of nitroaromatic radiosensitizers may originate in radiosensitizer/nitroreductase interaction. A study of two mammalian cell nitroreductases, xanthine oxidase and NADH cytochrome c reductase, shows that the efficiency of electron transfer is dependent on sensitizer electron affinity and not lipid solubility. Misonidazole and its demethylated metabolite (RO-05-9963), for example, are equally efficient as electron acceptors from xanthine oxidase. The only exception to the electron affinity correlation is m-nitrobenzamidine hydrochloride (MNBAM) which results because MNBAM inhibits electron donation to xanthine oxidase from its cofactor, xanthine. Allopurinol inhibits electron transfer and might be a useful adjuvant to the use of radiosensitizers. Evidence that allopurinol interacts with nitroreductases in vivo is deduced from the observation that allopurinol significantly alters the serum lifetimes in mice of misonidazole and RO-05-9963.
硝基芳香族放射增敏剂的正常组织毒性可能源于放射增敏剂/硝基还原酶的相互作用。对两种哺乳动物细胞硝基还原酶，即黄嘌呤氧化酶和NADH细胞色素c还原酶的研究表明，电子转移效率取决于增敏剂的电子亲和力而非脂溶性。例如，甲硝唑及其去甲基代谢物（RO-05-9963）作为黄嘌呤氧化酶的电子受体，效率相同。电子亲和力相关性的唯一例外是盐酸间硝基苯甲脒（MNBAM），这是因为MNBAM抑制了其辅因子黄嘌呤向黄嘌呤氧化酶的电子供体作用。别嘌呤醇抑制电子转移，可能是放射增敏剂使用的有用佐剂。别嘌呤醇在体内与硝基还原酶相互作用的证据是从以下观察结果推断出来的：别嘌呤醇显著改变了甲硝唑和RO-05-9963在小鼠体内的血清半衰期。
