Colon cancer chemoprevention by the anti-inflammatory drug, Quinacrine

抗炎药奎纳克林对结肠癌进行化学预防

• 批准号: 8624672
• 负责人: Lorne J Hofseth
• 金额: $ 7.03万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8624672
• 关键词: Adverse effects; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antimalarials; Antineoplastic Agents; Antioxidants; Apoptosis; Autoimmune Diseases; Autoimmune Process; Biological; Biological Response Modifier Therapy; Cells; Cessation of life; Chemoprevention; Childhood; Chronic; Clinical; Colitis; Colon Carcinoma; Complementary and alternative medicine; Crohn' s disease; Data; Development; Disease; Disease remission; FDA approved; Frequencies; Future; Giardiasis; Goals; Human; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Life; Life Style; Light; Malaria; Malignant Neoplasms; Modeling; Mus; Nitric Oxide; Patients; Pharmaceutical Preparations; Prevention; Property; Publishing; Quinacrine; Refractory; Research; Rheumatoid Arthritis; Systemic Lupus Erythematosus; TNF gene; Testing; Toxic effect; Treatment outcome; Ulcerative Colitis; Work; base; cancer chemoprevention; cancer prevention; cancer risk; colon carcinogenesis; conventional therapy; disorder prevention; efficacy testing; experience; human NOS2A protein; improved; in vivo; inhibitor/antagonist; mouse model; novel; prevent; public health relevance; small molecule; stem; therapeutic effectiveness

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.

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发病。由于最近对IBD的了解有所进展，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。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，我们专注于补充和替代药物，以及具有抗炎特性的小分子抑制剂。在这里，我们将测试一种小分子抗疟疾药物的假设，该药物之前被FDA批准用于治疗贾第虫病、疟疾和胶带虫感染，称为Quinacrine，可用于抑制结肠炎和预防结肠炎相关的结肠癌。这一假设的基本原理是：(a) Quinacrine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) Quinacrine可抑制iNOS诱导，促进炎症细胞凋亡。后一种理由源于我们发表的研究结果，即具有这些特性的药物（在体外抑制iNOS和驱动炎症细胞凋亡）可能在体内抑制结肠炎和预防结肠癌方面有效。本研究的结果将验证