Colon cancer prevention with non-systemic PDE5 inhibitors

今年美国约有5万人死于结直肠癌(CRC)，原因是 在诊断阶段，治疗基本上无效。因此，CRC的初级预防是非常重要的 对高危患者很重要。结直肠癌需要化学预防药物，但尚未获得批准 为了这个目的。广泛的临床前和流行病学证据表明，重新调整用途的希望很大 磷酸二酯酶-5抑制剂(PDE5I)用于结直肠癌的化学预防。PDE5i应用的障碍包括 全身给药引起的众多副作用和药物相互作用将减少 在其他健康人群中的遵从性。我们的目标是为CRC开发新型肠靶向PDE5i 高危人群的化学预防。 我们的中心假设是，西地那非的极性类似物将成为开发的理想的非系统性药物。 用于人类结直肠癌的初级化学预防的药物。我们的目标是(1)获得详细的 丙二酰西地那非和硼酰西地那非的体外药代动力学特性的信息，和(2)测定 这些类似物是否可以预防散发性结直肠癌小鼠模型的结肠癌。我们将测试我们的中央 假设，从而通过完成以下目标来实现本项目的目标： 目的1.验证西地那非的极性类似物与肠上皮细胞靶向PDE5i的假设。 目的2.验证西地那非的极性类似物对小鼠结肠癌的抑制作用。 通过在临床前CRC模型中提供详细的药代动力学信息和原则证明，我们的 该项目的科学影响将是为我们的极地PDE5i类似物的进一步开发扫清道路 用于结直肠癌初级化学预防的类药物。

Approximately 50,000 people will die from colorectal cancer (CRC) in the United States this year due to the late stage at diagnosis where treatments are largely ineffective. Primary prevention of CRC is therefore very important for high-risk patients. Chemoprevention agents are needed for CRC but nothing has been approved for this purpose. Extensive preclinical and epidemiological evidence show great promise for repurposing phosphodiesterase-5 inhibitors (PDE5i) for CRC chemoprevention. Barriers to this application of PDE5i include the numerous side effects and drug-drug interactions resulting from systemic delivery that would reduce compliance in an otherwise healthy population. Our goal is to develop novel gut-targeted PDE5i for CRC chemoprevention in people at high risk. Our central hypothesis is that polar analogs of sildenafil will make ideal non-systemic agents for developing into drugs for the primary chemoprevention of CRC in humans. Our objectives are (1) To gain detailed information about the pharmacokinetic properties of malonyl- and boronyl-sildenafil in vitro, and (2) to determine whether these analogs can prevent colon cancer in a mouse model of sporadic CRC. We will test our central hypothesis and thereby accomplish the objectives of this project by completing the following aims: Aim 1. Test the hypothesis that polar analogs of sildenafil behave as gut-epithelium targeted PDE5i. Aim 2. To test the hypothesis that polar analogs of sildenafil can inhibit colon cancer in mice. By providing detailed pharmacokinetic information and proof of principle in a preclinical CRC model, our project's scientific impact will be to clear the path for further development of our polar PDE5i analogs as first in class drugs for the primary chemoprevention of CRC.