Division of Biomedical Sciences, Edward Via College of Osteopathic Medicine, Virginia Tech Corporate Research Center, 2265 Kraft Drive, Blacksburg, VA 24060, USA.
Toxicology. 2011 Feb 27;280(3):71-6. doi: 10.1016/j.tox.2010.11.009. Epub 2010 Nov 27.
Mesalamine is the first line pharmacologic intervention for patients with ulcerative colitis, and recent epidemiologic studies have demonstrated a protective association between therapeutic use of the drug and colorectal carcinoma. However, the mechanism by which this protection is afforded has yet to be elucidated. Because copper is found at higher than normal concentrations in neoplastic cell nuclei and is known to interact with phenolic compounds to generate reactive oxygen species, we investigated whether the reaction of mesalamine/copper was able to induce oxidative DNA strand breaks in φX-174 RF I plasmid DNA, and the various components of the mechanism by which the reaction occurred. Plasmid DNA strand breaks were induced by pharmacologically relevant concentrations of mesalamine in the presence of a micromolar concentration of Cu(II), and damage was inhibited by bathocuproinedisulfonic acid (BCS) and catalase. Further, we showed that the reaction of copper with mesalamine consumed molecular oxygen, which was inhibited by BCS. Electron paramagnetic resonance spectral analysis of the reaction of copper/mesalamine indicated the presence of the hydroxyl radical, which was inhibited by both BCS and catalase. This study demonstrates for the first time that through a copper-redox cycling mechanism, the copper-mediated oxidation of mesalamine is a pro-oxidant interaction that generates hydroxyl radicals which may participate in oxidative DNA damage. These results demonstrate a potential mechanism of the anticancer effects of mesalamine in patients with ulcerative colitis.
美沙拉嗪是溃疡性结肠炎的一线药物治疗选择，最近的流行病学研究表明，该药物的治疗应用与结直肠癌之间存在保护关联。然而，其保护机制尚未阐明。由于铜在肿瘤细胞核中的浓度高于正常水平，并且已知其与酚类化合物相互作用生成活性氧，因此我们研究了美沙拉嗪/铜的反应是否能够诱导 φX-174 RF I 质粒 DNA 的氧化 DNA 链断裂，以及反应发生的各种机制成分。在微摩尔浓度的 Cu(II)存在下，美沙拉嗪在药理相关浓度下诱导质粒 DNA 链断裂，并且损伤被浴铜灵（BCS）和过氧化氢酶抑制。此外，我们表明，铜与美沙拉嗪的反应消耗了分子氧，BCS 抑制了这种消耗。铜/美沙拉嗪反应的电子顺磁共振光谱分析表明存在羟基自由基，BCS 和过氧化氢酶都抑制了其形成。本研究首次证明，通过铜氧化还原循环机制，铜介导的美沙拉嗪氧化是一种促氧化剂相互作用，可生成可能参与氧化 DNA 损伤的羟基自由基。这些结果表明了美沙拉嗪在溃疡性结肠炎患者中的抗癌作用的潜在机制。
