Development of a novel sulindac amide for colorectal cancer chemoprevention

描述（由申请人提供）：长期服用非甾体抗炎药（NSAIDs）可显著降低结直肠癌死亡风险。不幸的是，在所有个体中，环氧化酶（COX）抑制引起的毒性和对疾病进展的不完全保护限制了它们在化学预防中的应用。以往的研究表明，非甾体抗炎药的抗肿瘤活性不需要COX抑制，这使我们假设，通过设计出COX抑制活性，同时提高抗癌选择性，可以开发出更安全、更有效的衍生物。为了开发这种方法，我们使用分子模型来确定非甾体抗炎药sulindac sulfide （SS）的特定化学性质，这对COX-1和COX-2的结合至关重要。这些研究证明了羧酸部分的重要性，并提出了一种选择性破坏COX结合的策略。从一系列合成和筛选的衍生物中，发现了一种新的化合物sulindac sulfide amide (SSA)，尽管缺乏COX-1或COX-2的抑制活性，但它能有效抑制结肠肿瘤细胞增殖（IC50 = 1mM），选择性诱导结肠肿瘤细胞凋亡，并抑制血管生成。SSA具有理想的体内药理学特性，在小鼠中耐受性良好，尽管口服生物利用度有限，这需要高剂量才能达到体内抗肿瘤效果。尽管如此，在FCCC Min小鼠模型中，通过饮食给药SSA显著抑制结肠肿瘤的形成，抑制幅度大于80%。为了开发一种具有更好口服生物利用度的SSA制剂，我们发现市售的抗酸剂Maalox(R)可以显著提高SSA在HT-29异种移植小鼠模型中的吸收和抗肿瘤功效。在这里，我们建议优化SSA的配方，以获得高水平的化学预防功效（目标1）。然后将使用FCCC Min小鼠模型（目的2）以综合的方式评估SSA配方的疗效和毒性。在Aim 3中，将通过鉴定对SSA敏感和抗性的细胞系来研究SSA的分子靶点，这些细胞系将用于光亲和标记和全基因组微阵列分析。还将确定SSA在体外和体内对假定靶点表达的治疗效果，以及在肿瘤发生方面的潜在差异。拟议的研究将确定SSA是否是结肠直肠癌化学预防的临床候选药物，并将研究其抗肿瘤活性的分子靶点，我们怀疑这些靶点也可能参与结肠肿瘤的发生。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Nonsteroidal anti-inflammatory drugs display promising antineoplastic activity against colorectal cancer, although toxicity resulting from cyclooxygenase (COX) inhibition and incomplete protection from disease progression limits their use for chemoprevention. Evidence from our laboratory and other investigators suggest that the mechanism responsible for their antineoplastic activity does not require COX inhibition. These studies lead us to hypothesize that it may be feasible to develop safer and more efficacious NSAID derivatives that lack COX inhibitory activity, but have improved anticancer selectivity. In support of this hypothesis, we have identified a novel sulindac derivative, referred to as sulindac sulfide amide (SSA) that has potential safety and efficacy attributes for colorectal cancer chemoprevention. We propose to develop new formulations of SSA with improved pharmaceutical properties, conduct comprehensive animal studies to evaluate efficacy for colorectal cancer chemoprevention, and to identify the molecular target responsible for the unique anticancer properties of SSA. These studies are anticipated to result in a new drug candidate for clinical trials involving patients with familial or sporadic adenomatous polyposis who are at high risk of developing colorectal cancer.