Colon cancer chemoprevention by the anti-inflammatory drug, Quinacrine

描述(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)]的人患结肠癌的风险很高。IBDS是终生的，大约三分之一的患者在童年时期就开始了。由于对IBD认识的最新进展，免疫抑制剂(主要针对肿瘤坏死因子)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到重度IBD患者的临床状况，但这种积极的策略也有副作用，包括严重感染、癌症和死亡。因此，找到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，我们将测试一个假设，即一种已被FDA批准用于治疗贾第鞭毛虫病、疟疾和带虫感染的小分子抗疟疾药物，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。这一假设的基本原理是：(A)奎纳克林已被证明对自身免疫性、慢性炎症性疾病，如系统性红斑狼疮和类风湿性关节炎有效；(B)奎纳克林可以抑制iNOS的诱导，并促进炎症细胞的凋亡。后者的理论基础源于我们发表的研究结果，即具有这些特性(在体外抑制iNOS和促炎细胞凋亡)的药物在体内可能具有抑制结肠炎和预防结肠癌的效果。这项研究的结果将验证使用 奎纳克林治疗结肠炎和预防结肠癌，提供数据以更详细地探索奎纳克林起作用的机制(在未来的R01应用中)，并将另一种小分子(以前FDA批准用于某些条件)添加到越来越多的(小分子)列表中，这些小分子具有抑制人类结肠炎的高潜力，而不会出现目前已批准的IBD治疗方法的有害副作用。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.