Potent Topoisomerase I Inhibition For Glioma Therapy

描述(申请人提供)：DB-67是一种很有前途的新型硅胶 (硅喜树碱)类似物，其血液稳定性优于 FDA批准的喜树碱同系物拓扑替康和CPT-11.DB-67也 在体外和体内都显示出高度的抗癌效力。DB-67是 高亲脂性喜树碱和活性内酯水平在人体组织中持续存在 比现有FDA批准的喜树碱程度要高得多。DB-67具有 已由波拉克等人展示。比其他喜树碱更有效地对抗 胶质母细胞瘤细胞；在同一项研究中，该药物被发现非常有效 抗脑内植入的胶质母细胞瘤。对于此阶段I应用程序 有两个关键问题将得到解决。第一，脂质体制剂 需要进行研究，因为DB-67是高度亲油的，可能会在 注射部位，除非配方正确。因此，我们打算开发一种 具有理想稳定性和稳定性的冻干脂质体DB-67制剂 复悬浮液的微乳特性。其次，我们将测试我们的 人脑胶质瘤小鼠移植瘤模型系统中的脂质体制剂 确保DB-67配方表现出预期的功效概况。 DB-67已经在体外和体内得到了很好的探索；因此， 这一阶段的应用是寻找最佳配方，将DB-67推进到 通过深入研究各种脂质体配方进行临床试验。 建议的商业应用： FDA最初批准Comtothecins(拓扑替康和CPT-11)是在1996年。在……里面 1998年，FDA扩大了它们的使用范围，以适应新的适应症。与其他Campthecin 目前处于临床开发阶段，全球市场规模约为10亿美元 预计在不久的将来。我们的新型血液稳定喜树碱DB-67被描述为 在这一应用中可能呈现出比Campthecin药物更多的治疗优势 目前正在使用的，因此最终可能控制很大一部分 坎普特林市场。

DESCRIPTION (PROVIDED BY APPLICANT): DB-67 is a promising new silatecan (silylcamptothecin) analog that displays superior blood stability relative to the FDA-approved camptothecin congeners, topotecan and CPT- 11. DB-67 also exhibits a high degree of anti-cancer potency both in vitro and in vivo. DB-67 is a highly lipophilic camptothecin and active lactone levels persist in human tissues to a much greater degree than existing FDA-approved camptothecins. DB-67 has been shown by Pollack et al. to be more potent than other camptothecins against glioblastoma cells; in the same study the agent was found to be highly effective against intracranially implanted glioblastoma tumors. For this Phase I application there are two key issues that will be addressed. First, liposomal formulation studies are required as DB-67 is highly lipophilic and may crystallize at the site of injection unless properly formulated. Thus, we intend to develop a lyophilized liposomal DB-67 preparation that displays ideal stability and microemulsion characteristics upon re-suspension. Secondly, we will test our lead liposomal formulations in a human glioma xenograft murine model system to ensure that the DB-67 formulations exhibit the predicted efficacy profile. DB-67 has already been well explored in vitro and in vivo; thus, the intent of this Phase I application is to find the best formulation for advancing DB-67 to clinical trials by thoroughly studying various liposomal formulations. PROPOSED COMMERCIAL APPLICATION: Initial FDA approval of comptothecins (topotecan and CPT-11) occurred in 1996. In 1998 their use was expanded by the FDA for new indications. With other campthecins currently in clinical development, a worldwide market of approximately 1 billion dollars is anticipated in the near future. Our novel, blood-stable camptothecin, DB-67, described in this application may present several therapeutic advantages over the campthecin drugs that are currently used and, accordingly, could eventually control a significant portion of the campthecin market.