PDE Inhibition by Sulindac Sulfide Amide Derivatives for Lung Cancer Chemoprevention

舒林酸硫酰胺衍生物抑制 PDE 的肺癌化学预防作用

• 批准号: 8991313
• 负责人: Gary A Piazza
• 金额: $ 16.48万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991313
• 关键词: Amides; Antineoplastic Agents; Apoptosis; Apoptotic; Binding; Biological Availability; Cancer Patient; Carboxylic Acids; Cell Death; Cessation of life; Charge; Chemical Models; Chemicals; Chemoprevention; Cisplatin; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Colonic Neoplasms; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Data; Development; Disease; Epidemiologic Studies; FRAP1 gene; Generations; Growth; Health; Histopathology; Human; Implant; In Vitro; Incidence; Induction of Apoptosis; Intestines; Isoenzymes; Lung; Lung Neoplasms; Malignant - descriptor; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mammary Neoplasms; Mammary Tumorigenesis; Measures; Modeling; Molecular; Molecular Target; Mus; Non-Steroidal Anti-Inflammatory Agents; Oral; Oral Administration; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase II Clinical Trials; Plasma; Prevention; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Rattus; Reporting; Research Personnel; Risk; Rodent Model; Signal Transduction; Specificity; Specimen; Staging; Structure of parenchyma of lung; Sulfones; Sulindac; Sulindac Sulfide; Sulindac Sulfone; Tissues; Toxic effect; Tumor Tissue; amino group; analog; anticancer activity; base; cancer cell; cancer chemoprevention; cancer therapy; cancer type; cell growth; chemotherapy; cyclooxygenase 1; cyclooxygenase 2; docetaxel; drug candidate; improved; in vivo; lung tumorigenesis; mouse model; neoplastic cell; novel; novel therapeutics; phosphoric diester hydrolase; pre-clinical; preclinical study; programs; prostate carcinogenesis; screening; transgenic adenocarcinoma of mouse prostate; tumor; tumor xenograft; tumorigenesis; water solubility

 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.

 描述（由申请人提供）：流行病学研究提供了令人信服的证据，证明非甾体抗炎药（NSAID）可显著降低多种癌症类型（包括肺癌）的死亡率和风险。不幸的是，由于与环氧合酶（考克斯）抑制和抑制生理上重要的三尖杉酯碱相关的毒性，不推荐长期使用NSAID进行化学预防。然而，许多研究人员得出结论，涉及凋亡诱导的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凋亡的潜在途径来开发更安全和更有效的衍生物可能是可行的。从一个广泛的药物化学的努力，我们最近确定了一种新的舒林酸衍生物称为甲氧基-舒林酸硫酰胺（m-SSA），有效地和选择性地抑制肺肿瘤细胞的生长和诱导细胞凋亡在体外和肿瘤的发展在小鼠肺原位模型。机制研究表明，m-SSA抑制一种特异性磷酸二酯酶（PDE）同工酶，PDE 10在肺肿瘤细胞中升高，对其生长和存活至关重要。发现口服m-SSA耐受性良好，与血浆和其他组织相比，在肺中可达到高浓度。我们假设m-SSA具有独特的肺癌化学预防优势，并提出研究，以评估其疗效，毒性和作用机制的化学诱导的肺肿瘤发生的小鼠模型。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。这些探索性研究具有很高的潜力，通过确定一种安全有效的肺癌化学预防和肺癌治疗的临床候选药物来影响人类健康。