Development of a novel sulindac amide for colorectal cancer chemoprevention

摘要 长期服用非甾体类抗炎药（NSAID）可显著 降低结直肠癌的死亡风险。不幸的是，环氧合酶引起的毒性 (COX)在所有个体中对疾病进展的抑制和不完全保护限制了它们的使用 用于化学预防以前的研究表明，考克斯抑制剂是不需要的， NSAIDs的活性，这使我们假设开发更安全，更安全的NSAIDs可能是可行的。 通过设计出考克斯抑制活性，同时增强抗癌选择性，从而获得有效的衍生物。 为了开发这种方法，我们使用分子建模来确定 NSAID，舒林酸硫化物（SS），对考克斯-1和考克斯-2结合至关重要。这些研究 证明了羧酸部分的重要性，并提出了一种选择性地 破坏考克斯结合。从合成和筛选的一系列衍生物中， 一种被称为舒林酸硫酰胺（SSA）的化合物被鉴定为有效抑制结肠肿瘤 细胞增殖（IC 50 = 1 mM），选择性诱导结肠肿瘤细胞凋亡，并抑制 血管生成，尽管缺乏考克斯-1或考克斯-2抑制活性。SSA在体内具有理想的 药理学性质，并且在小鼠中耐受良好，尽管具有有限的口服生物利用度， 其需要高剂量以获得体内抗肿瘤功效。尽管如此， 该饮食显著抑制了FCCC Min小鼠模型中结肠肿瘤的形成， 百分之八十为了开发具有改善的口服生物利用度的SSA制剂，我们发现， 市售的抗酸剂Maalox（R）可明显增强抗酸剂的吸收和抗肿瘤功效， 在HT-29异种移植小鼠模型中的SSA。在这里，我们建议优化SSA的配方， 导致高水平的化学预防功效（目的1）。然后，SSA的这种公式将是 使用FCCC Min小鼠模型（Aim）以综合的方式评估功效和毒性 2）。在目标3中，将通过鉴定敏感和抗性细胞系来研究SSA的分子靶点 到SSA，将用于光亲和标记和全基因组微阵列分析。体外和 还将确定SSA对推定靶点表达的体内治疗效果， 在肿瘤发生方面的潜在差异。拟议的研究将确定SSA是否是一个 结肠直肠癌化学预防的临床候选人，并将研究分子靶点 我们怀疑它也可能参与结肠肿瘤的发生。

Abstract Long term administration of nonsteroidal anti-inflammatory drugs (NSAIDs) can significantly reduce the risk of death from colorectal cancer. Unfortunately, toxicity resulting from cyclooxygenase (COX) inhibition and incomplete protection from disease progression in all individuals, limits their use for chemoprevention. Previous studies suggest that COX inhibition is not required for the antineoplastic activity of NSAIDs, which led us to hypothesize that it may be feasible to develop safer and more effective derivatives by designing out the COX inhibitory activity, while enhancing anticancer selectivity. To develop this approach, we used molecular modeling to identify specific chemical properties of the NSAID, sulindac sulfide (SS) that are crucial for COX-1 and COX-2 binding. These studies demonstrated the importance of the carboxylic acid moiety and suggested a strategy to selectively disrupt COX binding. From a series of derivatives that were synthesized and screened, a novel compound referred to as sulindac sulfide amide (SSA) was identified that potently inhibits colon tumor cell proliferation (IC50 = 1mM), selectively induces apoptosis of colon tumor cells, and inhibits angiogenesis, despite lacking COX-1 or COX-2 inhibitory activity. SSA has desirable in vivo pharmacological properties and was well tolerated in mice, although has limited oral bioavailability, which requires high dosages for in vivo antitumor efficacy. Nonetheless, the administration of SSA by the diet significantly inhibited colon tumor formation in the FCCC Min mouse model by greater than 80%. To develop a formulation of SSA with improved oral bioavailability, we found that the commercially available antacid, Maalox(R) can appreciably enhance absorption and antitumor efficacy of SSA in the HT-29 xenograft mouse model. Here we propose to optimize a formulation for SSA that will result in a high level of chemopreventive efficacy (Aim 1). This formulation of SSA will then be evaluated for efficacy and toxicity in a comprehensive manner using the FCCC Min mouse model (Aim 2). In Aim 3, the molecular target of SSA will be studied by identifying sensitive and resistant cell lines to SSA that will be used for photo-affinity labeling and whole genome microarray analysis. In vitro and in vivo treatment effects of SSA on the expression of putative targets will also be determined as well as potential differences with regard to tumorigenesis. The proposed studies will determine if SSA is a clinical candidate for colorectal cancer chemoprevention and will investigate the molecular targets responsible for its antineoplastic activity that we suspect may also be involved in colon tumorigenesis.