PDE Inhibition by Sulindac Sulfide Amide Derivatives for Lung Cancer Chemoprevention

 描述(由申请人提供)：流行病学研究提供了令人信服的证据，证明非类固醇抗炎药(NSAIDs)可以显著降低多种癌症类型的发病率和死亡风险，包括肺癌。不幸的是，不建议长期使用非类固醇抗炎药进行化学预防，因为与抑制环氧合酶(COX)和抑制生理上重要的前列腺素有关的毒性。然而，许多研究人员已经得出结论，诱导细胞凋亡的COX非依赖性机制是其抗肿瘤活性的原因，这表明通过靶向导致细胞凋亡的潜在途径来开发更安全、更有效的衍生物可能是可行的。从广泛的药物化学工作中，我们最近发现了一种新的舒林酸衍生物，称为甲氧基舒林酸硫化物酰胺(m-SSA)，它能有效和选择性地抑制肺肿瘤细胞的生长，并在体外诱导细胞凋亡和小鼠肺原位模型的肿瘤发展。机制研究表明，m-SSA抑制一种特殊的磷酸二酯酶(PDE)同工酶PDE10，该同工酶在肺癌细胞中升高，对其生长和生存至关重要。与血浆和其他组织相比，m-SSA口服给药具有良好的耐受性，并可在肺部达到较高的浓度。我们假设m-SSA在肺癌的化学预防中具有独特的优势，并建议在化学诱导的小鼠肺肿瘤形成模型中评估其有效性、毒性和作用机制。将分析肺肿瘤的组织病理学、药物水平，并用于体内机制研究。这些探索性研究通过确定一种安全有效的肺癌化学预防和治疗的临床候选方案，具有很高的影响人类健康的潜力。

 DESCRIPTION (provided by applicant): Epidemiological studies provide compelling evidence that nonsteroidal anti-inflammatory drugs (NSAIDs) can significantly reduce the incidence and risk of death from multiple cancer types, including lung cancer. Unfortunately, the long-term use of NSAIDs for chemoprevention is not recommended because of toxicities associated with cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins. However, numerous investigators have concluded that a COX-independent mechanism involving apoptosis induction is responsible for their antineoplastic activity, suggesting it may be feasible to develop safer and more efficacious derivatives by targeting the underlying pathway leading to apoptosis. From an extensive medicinal chemistry effort, we recently identified a novel sulindac derivative referred to as methoxy-sulindac sulfide amide (m-SSA) that potently and selectively inhibits lung tumor cell growth and induces apoptosis in vitro and tumor development in a mouse lung orthotopic model. Mechanistic studies revealed that m-SSA inhibits a specific phosphodiesterase (PDE) isozyme, PDE10 that is elevated in lung tumor cells and essential for their growth and survival. Oral administration of m-SSA was found to be well tolerated and can achieve high concentrations in lungs compared with plasma and other tissues. We hypothesize that m-SSA has unique advantages for lung cancer chemoprevention and propose studies to evaluate its efficacy, toxicity, and mechanism of action in a mouse model of chemical-induced lung tumorigenesis. Lung tumors will be analyzed for histopathology, drug levels, and used for in vivo mechanistic studies. These exploratory studies have high potential to impact human health by identifying a safe and efficacious clinical candidate for lung cancer chemoprevention as well as for the treatment of lung cancer.