Development of a novel sulindac amide for colorectal cancer chemoprevention

摘要 长期服用非类固醇抗炎药(NSAIDs)可以显著 降低因结直肠癌死亡的风险。不幸的是，环氧合酶引起的毒性 (COX)抑制和不完全保护所有个体的疾病进展，限制了它们的使用 用于化学预防。以前的研究表明，COX抑制不是抗肿瘤所必需的 非甾体抗炎药的活性，这导致我们假设，开发更安全和更多的 通过设计环氧合酶抑制活性有效的衍生物，同时提高抗癌的选择性。 为了发展这种方法，我们使用分子建模来确定特定的化学性质 NSAID，舒林酸硫化物(SS)，对COX-1和COX-2结合至关重要。这些研究 论证了羧酸部分的重要性，并提出了一种选择性地 破坏COX结合。从一系列合成和筛选的衍生品中，一种新颖的 一种被称为舒林酸硫化物酰胺(SSA)的化合物被发现能有效地抑制结肠癌 细胞增殖(IC50=1 mM)，选择性诱导结肠癌细胞凋亡，并抑制 血管生成，尽管缺乏COX-1或COX-2抑制活性。SSA在体内具有可取的作用 药理特性，在小鼠中耐受性良好，尽管口服生物利用度有限， 这需要高剂量的体内抗肿瘤效果。尽管如此，SSA的管理由 饮食显著抑制fccc-Min小鼠模型中结肠癌的形成，其作用强于 80%。为了开发一种具有改善的口服生物利用度的SSA配方，我们发现 商用抗酸剂Maalox(R)可以显著增强以下物质的吸收和抗肿瘤效果 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，它将 产生高水平的化学预防效果(目标1)。然后，SSA的这个提法将是 使用Fccc Min小鼠模型(AIM)全面评估疗效和毒性 2)。在目标3中，将通过鉴定敏感和耐药细胞系来研究ssa的分子靶点。 将用于光亲和标记和全基因组微阵列分析的SSA。在体外和 还将确定SSA对假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 结直肠癌化学预防的临床候选对象并将研究分子靶点 负责其抗肿瘤活性，我们怀疑可能也参与了结肠肿瘤的发生。

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.