Verovski V N, Van den Berge D L, Soete G A, Bols B L, Storme G A
Department of Radiotherapy, Academic Hospital, Free University Brussels, Belgium.
Br J Cancer. 1996 Dec;74(11):1734-42. doi: 10.1038/bjc.1996.623.
A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.
一组8种人胰腺肿瘤细胞系表现出高度的内在辐射抗性，平均失活剂量在2.4至6.5 Gy之间，与黑色素瘤和胶质母细胞瘤报道的剂量相似。在细胞微球代谢诱导缺氧模型中评估了生物还原性一氧化氮供体硝普钠的放射增敏效力。0.1 mM的硝普钠显示出放射增敏作用，总体增强比为1.9，而氧气为2.5。放射增敏活性与辐射引起的单链DNA断裂增强相关。在细胞密度为3%至30%（v/v）的悬浮液中，硝普钠的半衰期从31分钟降至3.2分钟，表明微球的半衰期约为1分钟。尽管存在这种变化，但微球和稀释细胞悬浮液中的放射增敏活性相似。发现S-亚硝基-L-谷胱甘肽具有放射增敏活性，这与天然硫醇在储存源自硝普钠的放射生物学活性一氧化氮加合物中的可能作用一致。通过一氧化氮特异性微传感器测量，硝普钠通过生物还原而活化，而S-亚硝基-L-谷胱甘肽显示出大量自发分解。两种药物似乎都通过一氧化氮发挥放射增敏作用，因为其被羧基苯基四甲基咪唑啉氧基N-氧化物（羧基-PTI0）和氧合血红蛋白清除导致放射增敏作用减弱。硝普钠的效力至少比用作对照的2-硝基咪唑乙硝唑强10倍。我们的数据表明，目前用于治疗高血压的药物硝普钠是一种潜在的肿瘤放射反应调节剂。
