Develop a new cisplatin-based drug combination with reduced ototoxicity

项目摘要 尽管最近有新的药物开发，但基于铂的药物如顺铂仍然是不受欢迎的。 广泛用于治疗实体器官恶性肿瘤。除了有限的疗效外，严重的副作用 与顺铂的使用有关，如双侧和不可逆的听力损失。在 耳蜗，顺铂可以触发活性氧的产生，并激活其他几个 信号通路主要基于其抗氧化特性的各种试剂已经被用于制备抗氧化剂。 对顺铂诱导的耳毒性进行了测试。然而，它们中的许多显示出有限的功效，并且 干扰顺铂的治疗效果。广泛的体外研究表明， 氟桂利嗪（西比灵），一种阻断T型钙通道的药物，可以保护耳蜗细胞免受 顺铂诱导的细胞毒性。这种药物还具有很强的抗肿瘤活性， 癌症治疗的几个重要方面。我们的初步研究发现氟桂利嗪 在一种肺癌细胞系中，它可以与顺铂协同诱导细胞死亡， 噪音引起的听力损失基于这些发现，我们建议开发一种新的抗癌药物 通过测试氟桂利嗪是否可以与顺铂协同诱导癌细胞死亡， 同时预防顺铂引起的耳毒性。因为肺癌是导致 的癌症相关死亡，顺铂被广泛用于治疗这种疾病，在这里，我们将首先 测定氟桂利嗪和顺铂在两种肺癌细胞系A549和 H1975，并确定氟桂利嗪和顺铂在这些癌细胞中是否具有协同作用 当结合使用时（目标1）。我们将确定氟桂利嗪是否能预防顺铂- 在体内诱导耳毒性（目的2）。 简而言之，根据以前的研究和我们的初步数据，我们的项目目标是重新利用 氟桂利嗪与顺铂联合收割机治疗实体瘤，重点是肺癌。该项目将 生成对完成新药临床试验（IND）支持数据包非常重要的数据， 未来的临床研究最终目标是开发一种有效的癌症药物组合， 副作用.

PROJECT SUMMARY In spite of recent new drug developments, platinum-based drugs such as cisplatin are still widely used to treat solid organ malignancies. Besides its limited efficacy, serious side effects have been associated with the use of cisplatin, such as bilateral and irreversible hearing loss. In the cochlea, cisplatin can trigger the production of reactive oxygen species, and activate several other signaling pathways. A variety of agents, mainly based on their antioxidant properties, have been tested against cisplatin-induced ototoxicity. However, many of them show limited efficacies, and also interfere with the therapeutic effect of cisplatin. Extensive in vitro studies have indicated that flunarizine (Sibelium), a drug that blocks T-type calcium channels, can protect cochlear cells against cisplatin-induced cytotoxicity. This drug also has strong anti-tumor activities that act synergistically on several important aspects of cancer treatment. Our preliminary studies have found that flunarizine can synergistically induce cell death with cisplatin in one lung cancer cell line, and it can also protect noise-induced hearing loss. Based on these findings, we propose to develop a new cancer drug combination by testing whether flunarizine can synergistically induce cancer cell death with cisplatin, and at the same time, prevent cisplatin-induced ototoxicity. Because lung cancer is the leading cause of cancer-related death globally, and cisplatin is widely used to treat this disease, here, we will first determine the cytotoxic effects of flunarizine and cisplatin in two lung cancer cell lines: A549 and H1975, and determine whether flunarizine and cisplatin have synergistic effects in these cancer cells when used in combination (Aim 1). We will then determine whether flunarizine can prevent cisplatin- induced ototoxicity in vivo (Aim 2). In short, based on previous studies and our preliminary data, our project goal is to repurpose flunarizine to combine with cisplatin against solid tumors with a focus on lung cancer. This project will generate data important to complete an Investigational New Drug (IND)-enabling data package for future clinical studies. The ultimate goal is to develop an effective cancer drug combination with fewer side effects.