Development of a novel sulindac amide for colorectal cancer chemoprevention

描述(由申请人提供)：长期服用非类固醇抗炎药(NSAIDs)可以显著降低结直肠癌的死亡风险。不幸的是，环氧合酶(COX)抑制和对疾病进展的不完全保护在所有个体中产生的毒性限制了它们用于化学预防。以前的研究表明，NSAIDs的抗肿瘤活性并不需要COX抑制，这使得我们假设，通过设计COX抑制活性，同时提高抗癌选择性，开发更安全、更有效的衍生物是可行的。为了发展这一方法，我们使用分子模拟来确定NSAID的特定化学性质，舒林酸硫化物(SS)是COX-1和COX-2结合的关键。这些研究证明了羧酸部分的重要性，并提出了选择性阻断COX结合的策略。从合成和筛选的一系列衍生物中，鉴定出一种新的化合物，称为舒林酸硫化物(SSA)，它能有效地抑制结肠肿瘤细胞的增殖(IC50=1 mM)，选择性地诱导结肠肿瘤细胞的凋亡，并抑制血管生成，尽管缺乏COX-1或COX-2的抑制活性。SSA具有良好的体内药理作用，在小鼠体内耐受性良好，但口服生物利用度有限，需要高剂量才能达到体内抗肿瘤效果。尽管如此，饮食中给予SSA显著地抑制了fccc-Min小鼠模型中结肠癌的形成，抑制程度超过80%。为了开发一种提高口服生物利用度的SSA配方，我们发现商用抗酸剂Maalox(R)可以显著增强SSA在HT-29异种移植小鼠模型中的吸收和抗肿瘤效果。在这里，我们建议优化SSA的配方，以产生高水平的化学预防效果(目标1)。然后，将使用Fccc Min小鼠模型(Aim 2)以全面的方式评估SSA的这种配方的有效性和毒性。在目标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。此外，还将确定SSA在体外和体内对可能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是否为结直肠癌化学预防的临床候选药物，并将调查其抗肿瘤活性的分子靶点，我们怀疑这些靶点可能也参与了结肠癌的发生。 公共卫生相关性：非类固醇抗炎药显示了良好的抗结直肠癌活性，尽管环氧合酶(COX)抑制和对疾病进展的不完全保护导致的毒性限制了它们用于化学预防。来自我们实验室和其他研究人员的证据表明，导致它们抗肿瘤活性的机制不需要COX抑制。这些研究使我们假设，开发更安全、更有效的非甾体抗炎药衍生物是可行的，这些衍生物缺乏COX抑制活性，但具有更好的抗癌选择性。为了支持这一假设，我们已经确定了一种新的舒林酸衍生物，称为舒林酸硫化物酰胺(SSA)，它对结直肠癌的化学预防具有潜在的安全性和有效性。我们建议开发具有更好药理性能的SSA新制剂，进行全面的动物研究以评估其对结直肠癌化学预防的有效性，并确定与SSA独特的抗癌特性有关的分子靶点。这些研究有望产生一种新的候选药物用于临床试验，涉及家族性或散发性腺瘤性息肉病患者，他们有发展为结直肠癌的高风险。

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.