Kumar Binod, Kumar Amit, Pandey B N, Hazra Banasri, Mishra K P
Department of Pharmaceutical Technology, Jadavpur University, Calcutta, India.
Int J Radiat Biol. 2008 May;84(5):429-40. doi: 10.1080/09553000802030736.
Radio-resistance in tumor cells and associated escape from apoptotic mechanism is a major problem in clinical cancer radiotherapy. Therefore, as a strategy to enhance the apoptosis, a combination of radiation and tumor-selective cytotoxic agents might improve the efficacy of treatment. Thus, the radiomodifying potential of diospyrin diethylether (D7), a plant-derived antitumor agent, was studied in fibrosarcoma tumor, both in vitro and in vivo.
Mouse and human fibrosarcoma (Wehi164; HT1080) cells were treated with D7, alone, or in combination with radiation, for determination of cytotoxicity, clonogenic survival, and apoptotic death assays. Involvement of oxidative mechanism and nuclear factor kappa B (NF-kappaB) was studied in different treatment groups. In addition, fibrosarcoma-bearing mice were treated with D7 (intravenously, two doses, each of 1 mg/kg body weight) combined with radiation (two fractions of 2.5 Gy each) at appropriate intervals. The tumor volume was measured to assess 'tumor growth delay', and liver function enzymes in the serum of mice were estimated after the treatments.
A combination treatment with D7 and radiation showed enhancement in cytotoxicity and apoptotic induction and decrease in clonogenic survival of tumor cells, as compared to the treatments with the drug or radiation alone. Moreover, D7 in combination with radiation could significantly inhibit the radiation-induced NF-kappaB activation, and showed the generation of comparatively more intracellular reactive oxygen species (ROS). Similarly, a combination of D7 and radiation in vivo caused significant inhibition of tumor growth in vivo, and restoring the liver enzyme activity to the 'normal' level.
The combined treatment with quinonoid D7 and radiation caused increased cytotoxicity compared to single treatment with either agent alone in fibrosarcoma tumor systems, both in vitro and in vivo.
肿瘤细胞中的放射抗性以及相关的凋亡机制逃逸是临床癌症放射治疗中的一个主要问题。因此，作为增强凋亡的一种策略，放射与肿瘤选择性细胞毒性药物联合使用可能会提高治疗效果。因此，在体外和体内的纤维肉瘤肿瘤中研究了植物来源的抗肿瘤药物二氢异柿醌二乙醚（D7）的放射修饰潜力。
用D7单独或与放射联合处理小鼠和人纤维肉瘤（Wehi164；HT1080）细胞，以测定细胞毒性、克隆形成存活率和凋亡死亡检测。在不同治疗组中研究氧化机制和核因子κB（NF-κB）的参与情况。此外，给荷纤维肉瘤小鼠静脉注射D7（两剂，每剂1mg/kg体重），并在适当间隔联合放射（每次2.5Gy，分两次）。测量肿瘤体积以评估“肿瘤生长延迟”，并在治疗后估计小鼠血清中的肝功能酶。
与单独使用药物或放射治疗相比，D7与放射联合治疗显示肿瘤细胞的细胞毒性增强、凋亡诱导增加以及克隆形成存活率降低。此外，D7与放射联合可显著抑制放射诱导的NF-κB激活，并显示产生相对更多的细胞内活性氧（ROS）。同样，D7与放射在体内联合可显著抑制体内肿瘤生长，并使肝酶活性恢复到“正常”水平。
在体外和体内的纤维肉瘤肿瘤系统中，与单独使用任何一种药物相比，醌类D7与放射联合治疗导致细胞毒性增加。
