Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Int J Hyperthermia. 2011;27(5):435-44. doi: 10.3109/02656736.2011.578607.
Enediynes are potent inducers of DNA damage, but their clinical usefulness has been limited. Here we report the thermal enhancement of cytotoxicity of two novel metalloenediyne compounds at concentrations that are either not or minimally cytotoxic at 37°C, and present evidence regarding possible mechanisms for enhanced cytotoxicity.
HeLa cells were exposed to (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) (which becomes metallated in culture medium) or ((Z)-N,N'-bis[quinolin-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine)zinc(II) chloride (QuinED · ZnCl(2)) at 37°C or 42.5°C for 1 h, and clonogenic survival was compared after treatment at each temperature. Analyses of cell cycle progression and mode of death were performed after treatments.
Treatment with PyED or QuinED · ZnCl(2) resulted in a significant decrease in cell survival when cells were treated with drug at 42.5°C compared to 37°C. Enhanced cytotoxicity was attributed to increased apoptosis. However, perturbation of the cell cycle may also play a role. Cells which were only heated or exposed to PyED at 37°C experienced significant G(2)/M blocks that were eliminated when PyED and heat were administered simultaneously, suggesting that combined treatments override cell cycle arrests normally observed with each agent individually. Conversely, cells heated during treatment with QuinED · ZnCl(2) displayed an increased G(2)/M arrest compared to treatment at 37°C.
With improvements in site-specific heat delivery to tumours, systemic administration of non-toxic metalloenediynes coupled with localised hyperthermia may improve selective enediyne activation/targeting. Therefore PyED and QuinED · ZnCl(2), which show significantly enhanced cytotoxicity at elevated temperatures, may represent viable candidates for thermochemotherapy.
烯二炔类化合物是强有力的 DNA 损伤诱导剂，但由于其临床应用受限，目前尚未得到广泛应用。本研究报道了两种新型金属烯二炔化合物在浓度下的细胞毒性的热增强作用，这些浓度在 37°C 时要么没有表现出细胞毒性，要么仅有轻微的细胞毒性，并提供了增强细胞毒性的可能机制的证据。
将 HeLa 细胞暴露于（Z）-N，N'-双[1-吡啶-2-基-甲（E）-亚基]辛-4-烯-2,6-二炔-1,8-二胺（PyED）（在培养基中发生金属化）或[（Z）-N，N'-双[喹啉-2-基-甲（E）-亚基]辛-4-烯-2,6-二炔-1,8-二胺]锌（II）氯化物（QuinED·ZnCl(2)）在 37°C 或 42.5°C 下孵育 1 小时，并在每种温度下进行处理后比较克隆存活情况。处理后进行细胞周期进程和死亡方式分析。
与 37°C 相比，当细胞在 42.5°C 下用药物处理时，用 PyED 或 QuinED·ZnCl(2) 处理会导致细胞存活率显著下降。增强的细胞毒性归因于增加的细胞凋亡。然而，细胞周期的扰动也可能起作用。仅加热或在 37°C 下暴露于 PyED 的细胞经历了显著的 G(2)/M 阻滞，当同时给予 PyED 和热时，这种阻滞被消除，这表明联合治疗可以克服每个药物单独使用时观察到的细胞周期阻滞。相反，在用 QuinED·ZnCl(2) 处理期间加热的细胞与在 37°C 下处理相比，G(2)/M 阻滞增加。
随着肿瘤部位特异性热传递的改进，全身给予非毒性金属烯二炔类化合物与局部高热相结合可能会改善烯二炔类化合物的选择性激活/靶向作用。因此，在高温下显示出显著增强的细胞毒性的 PyED 和 QuinED·ZnCl(2) 可能是热化疗的可行候选物。
