IRON, NO, AND LIPID PEROXIDES IN PHOTODYNAMIC THERAPY

光动力疗法（PDT）是一种创新的癌症治疗方式 其基于肿瘤细胞的选择性体内或离体根除 通过局部光敏剂的作用。 继续 促进PDT技术和临床应用的发展 生物物理学和生物化学的理解的平行进展 影响其有效性的因素。初步调查结果表明， 铁和一氧化氮（NO）的效应作用具有重要的 对这一问题的影响，并为这一建议提供强有力的推动：㈠ 亲脂性螯合物形式的铁促进光动力脂质 当急性地呈现给白血病细胞时， 但是当长期呈现时，会产生强的光致电阻， 伴随铁蛋白诱导;（ii）铁刺激脂质 NO供体显著抑制过氧化和光毒性， 特别是当NO释放被光动力学增强时。 两 提出以下假说：（1）肿瘤组织铁营养状况是影响肿瘤发生的重要因素 在PDT反应性中，急性铁暴露促进细胞毒性， 放大脂质过氧化和慢性暴露逆转这种影响 通过铁蛋白的诱导。(2)肿瘤血管生成NO 细胞可以促进或抑制PDT细胞毒性，这取决于 超氧化物的可用性;抑制主要取决于NO的链- 破坏抗氧化作用。重点是光保护 铁和NO的影响，这些假设将进行测试，使用体内 （横纹肌肉瘤）和体外（白血病、乳腺肿瘤、内皮） 模型，两种PDT敏化剂，以及高性能 液相色谱电化学检测，电子自旋 共振自旋捕获、免疫印迹和带移电泳。 该计划旨在研究：（一）细胞对 光过氧化损伤和光杀伤反应的铁供体， （二）光致抗蚀剂的作用 铁刺激对细胞铁水平和表达/激活的影响 铁蛋白和其他铁响应蛋白;（iii） 光生NO对膜脂质过氧化和细胞杀伤的影响; (iv)细胞产生的NO对血管细胞光损伤的影响。这 这项工作是有意义的，因为它涉及新形式的光致电阻 铁和NO引起的。更好地了解这些反应将 对PDT疗效和设计问题有重要影响， 合理的PDT临床方案。

Photodynamic therapy (PDT) is an innovative cancer treatment modality that is based on selective in vivo or ex vivo eradication of tumor cells through the action of localized photosensitizing agents. Continued advances in PDT technology and clinical applications will be facilitated by parallel advances in understanding of the biophysical and biochemical factors which modulate its effectiveness. Preliminary findings pertaining to the effector actions of iron and nitric oxide (NO) have important bearing on this issue and provide a strong impetus for this proposal: (i) Iron in the form of lipophilic chelates promotes photodynamic lipid peroxidation and cell killing when presented acutely to leukemia cells, but elicits a strong photoresistance when presented chronically and this is accompanied by ferritin induction; (ii) Iron-stimulated lipid peroxidation and phototoxicity are markedly suppressed by NO donors, particularly when NO release is photodynamically enhanced. Two hypotheses are advanced: (1) Iron status of tumors is an important factor in PDT responsiveness, acute iron exposure promoting cytotoxicity by amplifying lipid peroxidation and chronic exposure reversing this effect through the induction of ferritin. (2) NO generated by tumor vascular cells can either promote or suppress PDT cytotoxicity, depending on superoxide availability; suppression depends largely on NO's chain- breaking antioxidant effects. With an emphasis on the photoprotective effects of iron and NO, these hypotheses will be tested, using in vivo (rhabdomyosarcoma) and in vitro (leukemia, breast tumor, endothelial) models, two PDT sensitizers, and techniques such as high-performance liquid chromatography with electrochemical detection, electron spin resonance-spin trapping, immunoblotting, and band-shift electrophoresis. The plan is to investigate: (i) cellular susceptibility to photoperoxidative damage and photokilling in response to iron donors such as hemin and methemoglobin; (ii) effects of photoresistance-conferring iron stimuli on cellular iron levels and expression/activation of ferritin and other iron-responsive proteins; (iii) effects of photogenerated NO on membrane lipid peroxidation and cell killing; and (iv) effects of cell-generated NO on photodamage to vascular cells. This work is significant because it deals with novel forms of photoresistance elicited by iron and NO. A better understanding of these responses would have important bearing on the question of PDT efficacy and the design of rational clinical protocols involving PDT.