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）]的人具有很高的结肠癌风险。 IBD 是终生的，大约三分之一的患者在儿童时期就开始患病。由于最近对 IBD 了解的进展，免疫抑制剂（主要针对 TNF）以及其他生物药物的使用频率不断增加。尽管这种方法改善了大多数中重度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。为了实现这一目标，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。在这里，我们将检验这样一个假设：一种已被 FDA 批准用于治疗贾第鞭毛虫病、疟疾和绦虫感染的小分子抗疟药物奎纳克林 (Quinacrine) 可用于抑制结肠炎并预防与结肠炎相关的结肠癌。这一假设的基本原理是： (a) 奎纳克林已被证明可有效对抗自身免疫性慢性炎症性疾病，例如系统性红斑狼疮和类风湿性关节炎； (b) 奎纳克林可以抑制 iNOS 诱导并驱动炎症细胞凋亡。后一个基本原理源于我们发表的研究结果，即具有这些特性（抑制 iNOS 并在体外驱动炎症细胞凋亡）的药物可能在体内抑制结肠炎和预防结肠癌方面有效。这项研究的结果将验证使用 奎纳克林对抗结肠炎和预防结肠癌，提供数据以更详细地探索奎纳克林的作用机制（在未来的 R01 应用中），并将另一种小分子（之前 FDA 批准用于某些条件）添加到不断增长的（小分子）列表中，该小分子具有很高的潜力抑制人类结肠炎，而不会产生当前批准的 IBD 治疗的有害副作用。这可能使数百万人受益。

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.