Ben-Yoseph O, Ross B D
Department of Radiology, University of Michigan, Ann Arbor 48109-0553.
Br J Cancer. 1994 Dec;70(6):1131-5. doi: 10.1038/bjc.1994.460.
Oxygen radicals induce cytotoxicity via a variety of mechanisms, including DNA damage, lipid peroxidation and protein oxidation. Here, we explore the use of a polyethylene glycol (PEG)-stabilised enzyme capable of producing reactive oxygen species (ROS), glucose oxidase (GO), for the purpose of harnessing the cytotoxic potential of ROS for treating solid tumours. PEG-GO (200 U), administered by two intratumoral injections 3 h apart, produced a significant growth delay in subcutaneous rat 9L gliomas as compared with control animals receiving heat-denatured PEG-GO. Rats were protected from systemic toxicity by subsequent i.v. administration of PEG-superoxide dismutase (PEG-SOD) and PEG-catalase. In vivo tumour metabolic changes, monitored using 31P magnetic resonance spectroscopy (31P-MRS) 6 h following initial administration of PEG-GO, revealed a 96 +/- 2% reduction in the ATP/Pi ratio and a 0.72 +/- 0.10 unit decline in intracellular pH. A 3-fold sensitisation of 9L glioma cells in vitro to hydrogen peroxide could be achieved by a 24 h preincubation with buthionine sulphoximine (BSO). This study suggests that oxidation therapy, the use of an intratumoral ROS-generating enzyme system for the treatment of solid tumours, is a promising area which warrants further exploration.
氧自由基通过多种机制诱导细胞毒性，包括DNA损伤、脂质过氧化和蛋白质氧化。在此，我们探索使用一种能够产生活性氧（ROS）的聚乙二醇（PEG）稳定化酶——葡萄糖氧化酶（GO），以利用ROS的细胞毒性潜力来治疗实体瘤。与接受热变性PEG-GO的对照动物相比，间隔3小时进行两次瘤内注射给予PEG-GO（200 U）可使皮下大鼠9L胶质瘤的生长显著延迟。随后通过静脉注射PEG-超氧化物歧化酶（PEG-SOD）和PEG-过氧化氢酶可保护大鼠免受全身毒性。在首次给予PEG-GO后6小时，使用31P磁共振波谱（31P-MRS）监测体内肿瘤代谢变化，结果显示ATP/Pi比值降低了96±2%，细胞内pH值下降了0.72±0.10个单位。通过用丁硫氨酸亚砜胺（BSO）预孵育24小时，可使9L胶质瘤细胞在体外对过氧化氢的敏感性提高3倍。本研究表明，氧化疗法，即使用瘤内ROS生成酶系统治疗实体瘤，是一个有前景的领域，值得进一步探索。
