Hofer K G, Lakkis M, Hofer M G
Institute of Molecular Biophysics, Florida State University, Tallahassee 32306.
Cancer. 1989 Apr 15;63(8):1501-8. doi: 10.1002/1097-0142(19890415)63:8<1501::aid-cncr2820630808>3.0.co;2-l.
Euoxic and hypoxic BP-8 murine sarcoma cells were exposed for up to 3 hours to various concentrations of three nitroimidazole derivatives (misonidazole, Ro 03-8799, RSU-1164) at normal or elevated incubation temperatures. Cell survival was monitored with the iodine 125 (125I)-iododeoxyuridine prelabeling assay. When cell lethality was evaluated as a function of drug molarity, the three nitroimidazoles displayed widely different toxicities, but when expressed in terms of toxicity ratio between euoxic and hypoxic cells, all three drugs showed nearly identical toxicity differentials of 16 to 18 in 1-hour drug incubation experiments. Prolonging the treatment period to 3 hours did not change the euoxic/hypoxic toxicity ratio for misonidazole and Ro 03-8799, but with RSU-1164 the toxicity ratio was increased significantly from 16 (1 hour) to 73 (3 hours). This increase was attributed to the bifunctional action of RSU-1164 as a combined electron-affinic and alkylating agent, with the alkylation component of cell killing becoming more pronounced after prolonged drug incubation under hypoxic conditions. Combined administration of hyperthermia and nitroimidazoles increased drug-induced cell lethality for all three agents, but did not materially change the relative toxicity differential between euoxic and hypoxic cells. In short, based on cellular toxicity data, Ro 03-8799 appears to offer no advantage over misonidazole as a selective cytocidal agent for hypoxic cells, but RSU-1164 does provide a moderate therapeutic advantage.
将常氧和低氧的BP - 8鼠肉瘤细胞在正常或升高的培养温度下，暴露于不同浓度的三种硝基咪唑衍生物（米索硝唑、Ro 03 - 8799、RSU - 1164）中长达3小时。用碘125（¹²⁵I）-碘脱氧尿苷预标记试验监测细胞存活情况。当根据药物摩尔浓度评估细胞杀伤力时，这三种硝基咪唑显示出广泛不同的毒性，但当以常氧和低氧细胞之间的毒性比表示时，在1小时药物培养实验中，所有三种药物均显示出几乎相同的毒性差异，为16至18。将治疗期延长至3小时，并未改变米索硝唑和Ro 03 - 8799的常氧/低氧毒性比，但对于RSU - 1164，毒性比从16（1小时）显著增加至73（3小时）。这种增加归因于RSU - 1164作为电子亲和性和烷基化联合剂的双功能作用，在低氧条件下长时间药物培养后，细胞杀伤的烷基化成分变得更加明显。热疗与硝基咪唑联合给药增加了所有三种药物诱导的细胞杀伤力，但并未实质性改变常氧和低氧细胞之间的相对毒性差异。简而言之，基于细胞毒性数据，作为低氧细胞的选择性杀细胞剂，Ro 03 - 8799似乎并不比米索硝唑具有优势，但RSU - 1164确实提供了一定的治疗优势。
