Colon cancer chemoprevention by the anti-inflammatory drug, Quinacrine

描述（由申请人提供）：患有炎症性肠病[IBD：溃疡性结肠炎（UC）和克罗恩病（CD）]的人具有高结肠癌风险。IBD是终身的，大约三分之一的患者在儿童时期开始。由于对IBD认识的最新进展，免疫抑制剂（主要针对TNF）以及其他生物药物的使用频率越来越高。虽然这种方法改善了大多数中度至重度IBD患者的临床状况，但这种积极的策略具有副作用，包括严重感染，癌症和死亡。因此，寻找毒性较小的方法来抑制结肠炎和预防结肠癌是当务之急。我们将重点放在补充和替代药物以及具有抗炎特性的小分子抑制剂上，以实现这一目标。在这里，我们将测试这样的假设，即一种已建立的小分子抗疟疾药物，以前被FDA批准用于治疗贾第虫病、疟疾和绦虫感染，称为奎纳克林，可以用于抑制结肠炎和预防与结肠炎相关的结肠癌。该假设的基本原理是：（a）已显示奎纳克林对自身免疫性慢性炎性疾病如系统性狼疮性肾炎和类风湿性关节炎有效;和（B）奎纳克林可抑制iNOS诱导并驱动炎性细胞的凋亡。后一个理由源于我们发表的发现，即具有这些特性（抑制iNOS并驱动体外炎性细胞凋亡）的药物可能在体内抑制结肠炎和预防结肠癌方面具有疗效。本研究的结果将验证 Quinacrine对抗结肠炎和结肠癌预防，提供数据以更详细地探索Quinacrine的机制（在未来的R 01应用中），并将另一种小分子（先前FDA批准用于某些条件）添加到越来越多的（小分子）列表中，这些小分子具有很高的抑制人类结肠炎的潜力，而没有目前批准的IBD治疗的有害副作用。这可能会使数百万人受益。

DESCRIPTION (provided by applicant): People with inflammatory bowel disease [IBD: ulcerative colitis (UC) and Crohn's disease (CD)] have a high colon cancer risk. IBDs are life-long, and start in about one third of patients during childhood. Due to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNF¿), as well as other biological drugs, are being used with increasing frequency. Although this approach has improved the clinical condition of the majority of patients with moderate to severe IBD, this aggressive strategy has side effects, including severe infection, cancer and death. Therefore, finding less toxic means to suppress colitis and prevent colon cancer are of high priority. We have focused our efforts on complementary and alternative medicines, as well as small molecule inhibitors with anti-inflammatory properties to accomplish this goal. Here, we will test the hypothesis that an established small molecule anti- malarial drug, previously FDA approved for the treatment of giardiasis, malaria, and tape-worm infection, called Quinacrine, can be used to suppress colitis and prevent colon cancer associated with colitis. The rationale for this hypothesis is: (a) Quinacrine has been shown to be effective against autoimmune, chronic inflammatory diseases such as systemic lupus erythematosis, and rheumatoid arthritis; and (b) Quinacrine can suppress iNOS induction and drive apoptosis of inflammatory cells. The latter rationale stems from our published findings that agents having these properties (suppress iNOS and drive apoptosis of inflammatory cells in vitro) are likely to have efficacy in the suppression of colitis and prevention of colon cancer in vivo. Results from this study will validate the use of Quinacrine against colitis and in colon cancer prevention, provide data to explore in more detail the mechanisms by which Quinacrine does this (in a future R01 application), and add another small molecule (previously FDA approved for certain conditions) to a growing list (of small molecules) that have a high potential to suppress colitis in humans without the detrimental side effects of current approved treatments for IBD. This can potentially benefit millions of people.