Walicka M, Szmigiero L, Ciesielska E, Gradzka I
Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
Biochem Pharmacol. 1993 Aug 17;46(4):615-20. doi: 10.1016/0006-2952(93)90546-9.
Nitracrine (Ledakrin, 1-nitro-9-(3,3-N,N-dimethylaminopropylamino)-acridine) is of interest as a DNA intercalator and alkylator with very high cytotoxic potency, especially against hypoxic cells. DNA-DNA crosslinks [Konopa et al., Chem Biol Interact 43: 175-197, 1983; Pawlak et al., Cancer Res 44: 4289-4296, 1984] or DNA-protein crosslinks (DPCs) [Woynarowski et al., Biochem Pharmacol 38: 4095-4101, 1989; Szmigiero and Studzian, Biochim Biophys Acta 1008: 339-345, 1989] are related to the toxicity of the drug. The cytotoxic effect of and DNA damage induced by nitracrine were measured in two sublines of mouse lymphoma L5178Y, LY-R (resistant to ionizing radiation) and LY-S (sensitive to ionizing radiation). LY-R cells were more sensitive to nitracrine (D10 = 0.11 microM) than LY-S (D10 = 0.35 microM) when treated for 1 hr at 37 degrees. To a DNA-DNA crosslinking agent, mitomycin C, the comparative sensitivity was opposite. LY-R cells were more resistant to this drug than LY-S cells (D10 = 7.1 vs 2.3 microM). DNA damage induced by nitracrine was measured by the alkaline elution method and by nitrocellulose filter binding assay. Nitracrine treatment with biologically relevant concentrations (0.1-3.0 microM, 1 hr, 37 degrees) induced only DPCs. Interstrand crosslinks and DNA breaks were not detected. Nitracrine produced about two times more DPCs in LY-R cells than in LY-S cells. Both sublines removed 50% of initial lesions during 2 hr post-treatment incubation. The greater sensitivity of LY-R cells to nitracrine is thus not related to the efficiency of DNA repair, but may be a consequence of enhanced initial damage in the form of DPCs. This finding is consistent with the latter lesion being responsible for the cytotoxicity of nitracrine.
尼曲吖啶（雷达克林，1-硝基-9-(3,3-二甲基氨基丙基氨基)-吖啶）作为一种DNA嵌入剂和烷化剂备受关注，其细胞毒性非常高，尤其对缺氧细胞。DNA-DNA交联[科诺帕等人，《化学生物学相互作用》43: 175 - 197，1983；帕夫拉克等人，《癌症研究》44: 4289 - 4296，1984]或DNA-蛋白质交联（DPCs）[沃伊纳罗夫斯基等人，《生物化学与药物学》38: 4095 - 4101，1989；斯米格耶罗和斯图齐安，《生物化学与生物物理学报》1008: 339 - 345，1989]与该药物的毒性有关。在小鼠淋巴瘤L5178Y的两个亚系LY-R（对电离辐射有抗性）和LY-S（对电离辐射敏感）中测量了尼曲吖啶的细胞毒性作用和诱导的DNA损伤。当在37℃处理1小时时，LY-R细胞比LY-S细胞（D10 = 0.35微摩尔）对尼曲吖啶更敏感（D10 = 0.11微摩尔）。对于DNA-DNA交联剂丝裂霉素C，比较敏感性则相反。LY-R细胞比LY-S细胞对这种药物更具抗性（D10 = 7.1对2.3微摩尔）。通过碱性洗脱法和硝酸纤维素滤膜结合试验测量了尼曲吖啶诱导的DNA损伤。用生物学相关浓度（0.1 - 3.0微摩尔，1小时，37℃）处理尼曲吖啶仅诱导了DPCs。未检测到链间交联和DNA断裂。尼曲吖啶在LY-R细胞中产生的DPCs比在LY-S细胞中多约两倍。在处理后2小时的孵育期间，两个亚系都消除了50%的初始损伤。因此，LY-R细胞对尼曲吖啶的更高敏感性与DNA修复效率无关，而可能是DPCs形式的初始损伤增强的结果。这一发现与后一种损伤是尼曲吖啶细胞毒性的原因一致。
