2-Nitroimidazole potentiation of nitrosourea induced cytotoxicity in subcutaneous implants of rat 9L brain tumor cells.
2-Nitroimidazole potentiation of nitrosourea induced cytotoxicity in subcutaneous implants of rat 9L brain tumor cells.
复制标题
2-硝基咪唑增强亚硝基脲诱导的大鼠 9L 脑肿瘤细胞皮下植入物的细胞毒性。
DOI：
10.1007/bf00166993
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发表时间：
1991
影响因子：
3.9
通讯作者：
Wheeler,KT
中科院分区：
文献类型：
--
作者：
Wong,KH;Wallen,CA;Wheeler,KT
为了确定脑肿瘤化学增效试验中是否应根据已知的结构-活性关系（电子亲和力、亲脂性、烷基化活性、氨基甲酰化活性）选择 2-硝基咪唑 (2-NI) 和亚硝基脲 (NU)，s.c.大鼠 9L 脑肿瘤细胞植入物在有氧和缺氧条件下联合使用米索硝唑 (MISO) 或依他硝唑 (SR-2508)，以及在有氧条件下施用 BCNU、CCNU 或氯脲菌素 (CLZ) 进行处理。通过体内体外集落形成测定来评估细胞杀灭。为了模拟“预孵育效应”，腹腔注射 2-NI，30 分钟后夹住肿瘤。 2小时后，松开夹子，立即施用NU。 MISO (2.5 mmol/kg) 和 SR-2508 (3.75 mmol/kg) 在 30 分钟内达到相同的峰值肿瘤浓度。两种 2-NI 在被夹紧的肿瘤中以相同的速率代谢；然而，在 2 小时的钳夹期内，缺氧细胞对 2-NI 的代谢并未产生任何可测量的皮下细胞。 9L细胞杀伤。 NU 杀死皮下氧气的相对有效性。 9L肿瘤细胞为：BCNU>CCNU>CLZ。在 NU 给药前夹住肿瘤不会改变 NU 细胞毒性。在含氧肿瘤中没有观察到 2-NI 增强 NU 细胞毒性。尽管缺氧细胞对 MISO 的代谢不会导致任何剂量下 CLZ 细胞毒性的增强，但会导致所有剂量下 BCNU 细胞毒性的增强以及高剂量下 CCNU 细胞毒性的增强。缺氧细胞对 SR-2508 的代谢在任何剂量下均不会导致 BCNU、CCNU 或 CLZ 细胞毒性增强。这些原位数据表明，1) MISO 在增强 NU 细胞毒性方面优于 SR-2508，2) 脑肿瘤化学增强试验中的 NU 的选择应基于它是针对特定类型脑肿瘤的最有效的潜在 NU。
To determine if the 2-nitroimidazole (2-NI) and the nitrosourea (NU) in a brain tumor chemopotentiation trial should be selected on the basis of known structure-activity relationships (electron affinity, lipophilicity, alkylating activity, carbamoylating activity), s.c. implants of rat 9L brain tumor cells were treated with combinations of misonidazole (MISO) or etanidazole (SR-2508) administered under oxic and hypoxic conditions, and BCNU, CCNU or chlorozotocin (CLZ) administered under oxic conditions. Cell kill was assessed by anin vivotoin vitrocolony formation assay. To mimic the ‘preincubation effect’, the 2-NI was injected i.p., and 30min later the tumor was clamped. After 2hr, the clamp was released, and the NU administered immediately. MISO (2.5 mmole/kg) and SR-2508 (3.75 mmole/kg) reached the same peak tumor concentration in 30 min. Both 2-NIs were metabolized at the same rate in the clamped tumors; however, metabolism of the 2-NIs by hypoxic cells over the 2hr clamping period did not produce any measurable s.c. 9L cell kill. The relative effectiveness of the NUs for killing oxic s.c. 9L tumor cells was: BCNU > CCNU > CLZ. Clamping the tumor prior to NU administration did not change the NU cytotoxicity. No potentiation of the NU cytotoxicity by the 2-NIs was observed in oxic tumors. Although metabolism of MISO by hypoxic cells did not result in potentiation of CLZ cytotoxicity at any dose, it resulted in potentiation of BCNU cytotoxicity at all doses and CCNU cytotoxicity at high doses. Metabolism of SR-2508 by hypoxic cells did not result in potentiation of BCNU, CCNU or CLZ cytotoxicity at any dose. Thesein situdata indicate that, 1) MISO is superior to SR-2508 for potentiating NU cytotoxicity, and 2) the NU in a brain tumor chemopotentiation trial should be selected on the basis that it is the most effective potentiable NU against a particular type of brain tumor.