Potent Topoisomerase I Inhibition For Glioma Therapy

性状（由申请人提供）：DB-67是一种有前途的新型硅替康 （甲硅烷基喜树碱）类似物，相对于 FDA批准的喜树碱同系物拓扑替康和CPT- 11。DB-67 在体外和体内均表现出高度的抗癌效力。DB-67是 高度亲脂性喜树碱和活性内酯水平在人体组织中持续存在 比现有的FDA批准的喜树碱更大的程度。DB-67具有 Pollack等人已证明比其他喜树碱更有效， 胶质母细胞瘤细胞;在同一项研究中，该药物被发现是非常有效的 对抗颅内植入的胶质母细胞瘤 对于第一阶段应用 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是高度亲脂性的， 注射部位，除非配方正确。因此，我们打算开发一个 冻干的脂质体DB-67制剂显示出理想的稳定性， 再悬浮时的微乳液特性。其次，我们将测试我们的 在人神经胶质瘤异种移植鼠模型系统中， 确保DB-67制剂表现出预测的功效特征。 DB-67已经在体外和体内进行了很好的研究;因此， 第一阶段的应用是为了找到最佳配方，使DB-67能够 通过深入研究各种脂质体制剂进行临床试验。 拟定商业应用： 1996年，FDA首次批准了喜树碱（托泊替康和CPT-11）。 在 1998年，FDA将其用于新的适应症。 与其他campthecins 目前处于临床开发阶段，全球市场约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描述了 与喜树碱药物相比 目前正在使用，因此，最终可能控制相当大一部分的 campthecin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.