Department of Surgery/Neurosurgery and School of Medicine, Duke University and Medical Center, Durham, North Carolina 27710, USA.
Int J Radiat Biol. 2010 Feb;86(2):145-63. doi: 10.3109/09553000903419965.
We examined the effects of manganese (III) meso-tetrakis (diethyl-2-5-imidazole) porphyrin, a metalloporphyrin antioxidant (MPA), on neural tissue radiation toxicity in vivo and on tumour cell radiosensitivity in vitro.
MPA was administered directly into the right lateral ventricle of young adult, male Sprague-Dawley rats (0 or 3.4 microg) 3 h before treatment with a single fraction, 100 Gy radiation dose delivered to the left brain hemisphere. The effects of treatment on radiation responses were assessed at different time points following irradiation.
MPA treatment prior to brain irradiation protected against acute radiation-induced apoptosis and ameliorated delayed damage to the blood-brain barrier and radiation necrosis, but without producing a discernible increase in tissue superoxide disumtase (SOD) activity. In vitro, MPA pretreatment protected against radiation-induced apoptosis in primary neuronal cultures and increased clonogenic survival of irradiated rat glioma C6 cells, but had no discernible effect on radiation-induced DNA double-strand breaks. MPA, a low molecular weight SOD mimic, significantly increased mitochondrial SOD activity in C6 cells, but not total cellular SOD activity. MPA up-regulated C6 expression of heme-oxygenase 1 (HO-1), an endogenous radioprotectant, but had no effect on HO-1 levels in human astrocytoma U-251 cells, human prostatic carcinoma LNCaP cells, or primary rat brain microvascular endothelial cells in vitro, nor on brain tissue HO-1 expression levels in vivo.
Metalloporphyrin antioxidants merit further exploration as adjunctive radioprotectants for cranial radiotherapy/radiosurgery applications, although the potential for tumour protection must be carefully considered.
我们研究了锰（III）meso-四（二乙基-2-5-咪唑）卟啉，一种金属卟啉抗氧化剂（MPA），对体内神经组织放射毒性和体外肿瘤细胞放射敏感性的影响。
MPA 在单次 100Gy 左半脑照射前 3 小时直接注入年轻成年雄性 Sprague-Dawley 大鼠右侧侧脑室（0 或 3.4μg）。在照射后不同时间点评估治疗对放射反应的影响。
MPA 治疗可预防急性放射诱导的细胞凋亡，并改善血脑屏障和放射性坏死的迟发性损伤，但不会导致组织超氧化物歧化酶（SOD）活性明显增加。在体外，MPA 预处理可防止原代神经元培养物中放射诱导的细胞凋亡，并增加照射大鼠神经胶质瘤 C6 细胞的克隆存活能力，但对放射诱导的 DNA 双链断裂无明显影响。MPA 是一种低分子量 SOD 模拟物，可显著增加 C6 细胞的线粒体 SOD 活性，但不增加总细胞 SOD 活性。MPA 上调 C6 血红素加氧酶 1（HO-1）的表达，HO-1 是一种内源性放射保护剂，但对人星形细胞瘤 U-251 细胞、人前列腺癌细胞 LNCaP 细胞或原代大鼠脑微血管内皮细胞中的 HO-1 水平无影响，也对体内脑组织 HO-1 表达水平无影响。
金属卟啉抗氧化剂作为颅放疗/放射外科应用的辅助放射保护剂值得进一步研究，尽管必须仔细考虑肿瘤保护的潜力。
