Mulcahy R T, Carminati A, Barascut J L, Imbach J L
Department of Human Oncology, University of Wisconsin, Madison 53792.
Cancer Res. 1988 Feb 15;48(4):798-801.
The cytotoxicity of two series (A and B) of novel mixed-function compounds (NI-CENU) combining nitroimidazole (NI) and chloroethylnitrosourea (CENU) functions were examined in Mer- HeLa-MR and Mer+ HeLa-S3 cells. Series A compounds differed from those in Series B by having a hydroxypropyl as opposed to an ethyl group linking the imidazole ring and the nitrosoureido function. Four analogues, including the imidazole and the 2-, 4-, and 5-NO2 derivatives, were evaluated in each series. Cells were exposed to the various compounds for 4 h under aerobic and hypoxic conditions, and toxicity was assessed by clonogenic assay. Corresponding analogues in Series A and B were equally toxic to HeLa-MR cells. Preferential hypoxic toxicity was observed only with the 2-NO2 derivative in either series (I-278, Series A; I-282, Series B). For either compound a dose enhancement factor of 2.4 was observed for hypoxic exposures. The Mer+ HeLa-S3 cells were considerably more resistant to the NI-CENU than were their HeLa-MR counterparts. In further contrast to the HeLa-MR data, the Series B compounds were consistently more effective against the HeLa-S3 cells than were their corresponding Series A analogues. The enhanced effectiveness of the Series B compounds in HeLa-S3 cells may be related to the fact that these compounds express carbamoylating activity whereas Series A compounds lack this property. Again only I-278 and I-282 were preferentially toxic to hypoxic cells; however, the aerobic/hypoxic differential was dramatically reduced (dose enhancement factor = 1.3) as compared to that observed with the HeLa-MR cells. The enhanced hypoxic toxicity of the 2-NO2 NI-CENUs was not due to direct hypoxic toxicity of the nitro moiety but presumably is the result of enhancement of CENU toxicity (i.e., chemosensitization). The data suggest that much lower concentrations of NI may be required to observe chemosensitization when the NI and chemotherapeutic agent are administered as a single mixed-function compound.
在Mer-HeLa-MR和Mer+ HeLa-S3细胞中检测了结合硝基咪唑（NI）和氯乙基亚硝基脲（CENU）功能的两个系列（A和B）新型混合功能化合物（NI-CENU）的细胞毒性。A系列化合物与B系列化合物的不同之处在于，连接咪唑环和亚硝基脲功能的是羟丙基而非乙基。每个系列评估了四种类似物，包括咪唑以及2-、4-和5-NO₂衍生物。细胞在有氧和缺氧条件下暴露于各种化合物4小时，并通过克隆形成试验评估毒性。A系列和B系列中的相应类似物对HeLa-MR细胞的毒性相同。仅在任一系列的2-NO₂衍生物（A系列中的I-278；B系列中的I-282）中观察到优先缺氧毒性。对于任一化合物，缺氧暴露的剂量增强因子为2.4。Mer+ HeLa-S3细胞对NI-CENU的抗性比HeLa-MR细胞强得多。与HeLa-MR数据进一步不同的是，B系列化合物对HeLa-S3细胞的作用始终比其相应的A系列类似物更有效。B系列化合物在HeLa-S3细胞中有效性增强可能与这些化合物具有氨甲酰化活性而A系列化合物缺乏此特性这一事实有关。同样，只有I-278和I-282对缺氧细胞具有优先毒性；然而，与HeLa-MR细胞相比，需氧/缺氧差异显著降低（剂量增强因子 = 1.3）。2-NO₂ NI-CENU增强的缺氧毒性并非由于硝基部分的直接缺氧毒性，推测是CENU毒性增强（即化学增敏）的结果。数据表明，当NI和化疗药物作为单一混合功能化合物给药时，可能需要低得多的NI浓度才能观察到化学增敏作用。
