RADIOLYSIS, PHOTOLYSIS AND SONOLYSIS OF CELLS AND THEIR CONSTITUENTS

细胞及其成分的放射分解、光分解和声分解

• 批准号: 2464439
• 负责人: P RIESZ
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2464439
• 关键词: amidines; azo compounds; combination cancer therapy; cyanides; cytolysis; drug interactions; electron spin resonance spectroscopy; free radical oxygen; free radical scavengers; neoplasm /cancer photoradiation therapy; nonvisual photosensitivity; photolysis; photosensitizing agents; porphyrins; radiosensitizer; temperature; tissue /cell culture; ultrasound biological effect; ultrasound therapy

Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effect on cell killing by the combination of a drug (a sonosensitizer) and ultrasound. We have demonstrated sonodynamic toxicity of low concentrations (greater than or equal to 1 microM) of gallium porphyrin ATX-70 in human leukemia HL-525 cells exposed to 50 kHz ultrasound. The mechanism of this ATX-70 - dependent sonosensitization is unknown, but we have established the requirement of extracellular, rather than intracellular, localization of ATX-70 molecules for sonosensitization. Short-lived toxic intermediates produced from ATX-70 by ultrasound are implicated in the mechanism. We are currently exploring the possibility that pi-radicals are involved in the mechanism for sonosensitization by porphyrins. We have studied molecular mechanisms of sonochemical activation of new promising sonodynamic conpounds - organic azocompounds. These compounds were investigated previously as hyperthermia sensitizers, due to their ability to decompose thermally to yield reactive peroxyl radical intermediates capable of cell damage. Using electron paramagnetic resonance spectroscopy and the spin trap DMPO we have demonstrated formation of oxygen-centered radical intermediates from 2,2'azobis (N,N'-dimethyleneisobutyramidine) dihydrochloride (VA-044), 2-(carbomoylazo)-isobutyronitrile (V-30), and 2,2'azobis (2-amidinopropane-dihydrochloride (AAPH). While VA-044 and AAPH could also produce radicals at about 40 degrees C, radical decomposition of V-30 is ultrasound-specific in the range of physiological temperatures. Hence, V-30 appears to be a promising sonosensitizer, which could be decomposed site-specifically using a focused ultrasound beam, thus limiting undesirable damage to tissues outside the focused ultrasound beam.

声动力疗法是一种有前途的新的癌症治疗方式， 通过药物（a）和（b）的组合对细胞杀伤的协同作用， 声敏剂）和超声。 我们已经证明了声动力学毒性 低浓度（大于或等于1 μ M）的镓 50 kHz下人白血病HL-525细胞中的ATX-70卟啉 超声. 这种ATX-70依赖性声敏作用的机制是 未知，但我们已经建立了细胞外的要求，而不是 ATX-70分子的细胞内定位， 声致敏 ATX-70产生的短期毒性中间体 与该机制有关。 我们目前正在探索 π-自由基参与的可能性， 卟啉的声敏作用。 我们已经研究了 新型声动力化合物--有机物声化学活化 偶氮化合物。 这些化合物以前被研究为 热疗敏化剂，由于它们能够热分解， 产生能够损伤细胞的活性过氧自由基中间体。 使用电子顺磁共振谱和自旋陷阱DMPO 我们已经证明了氧中心自由基中间体的形成 由2，2 '-偶氮二（N，N'-二亚甲基异丁脒）二盐酸盐 （VA-044）、2-（氨基甲酰基偶氮）-异丁腈（V-30）和2，2 '-偶氮二 （2-脒基丙烷-二盐酸盐（AAPH）。 而VA-044和AAPH可以 也产生自由基在约40摄氏度，自由基分解的V-30 在生理温度范围内是超声特异性的。 因此，我们认为， V-30是一种很有前途的声敏剂， 使用聚焦超声波束，从而限制 对聚焦超声波束之外的组织造成不希望的损伤。