Use of Beta-Lapachone for Lung Cancer Chemotherapy

描述（由申请人提供）： 肺癌是美国癌症死亡的主要原因。非小细胞肺癌（NSCLC）占诊断肺癌的75%以上。目前的化疗方案对NSCLC无效，五年生存率仅为14%。利用癌症特异性靶点的方案，特别是增加治疗指数的方案，应能提高患者的生存率。我们假设，β-拉帕酮（β-lap），一种选择性杀死具有升高水平的双电子还原酶NAD（P）H：醌氧化还原酶1（NQOI）的癌细胞的药物，将是一种有效的药物，用于对抗特异性过表达这种生物活化酶的NSCLC细胞。β-lap引起的细胞死亡不依赖于细胞周期状态，不依赖于p53、pRb或半胱天冬酶，下游细胞死亡事件与钙蛋白酶介导的细胞凋亡一致。更重要的是，由β-lap引起的细胞死亡依赖于NQO 1表达，其中NQO 1缺陷细胞对药物具有抗性，用NQO 1校正细胞恢复致死性，并且联合施用双香豆素（一种NQO 1抑制剂）防止致死性。NQOI在人NSCLC中通常升高4至大于100倍，表明β-lap用于治疗这种疾病。最近开发的新型给药方法使得在动物模型中给予该药物以确定对NSCLC的疗效成为可能。三个目标将检验这一假设： 目的1：评价NQO 1在NSCLC细胞中β-lap介导的细胞死亡中的作用，并开发 用于未来治疗的实验室相关性。（1-3年级）。目标二：开发用于β-lap的药物载体，其可以将药物局部递送至肺，或者利用允许载体-药物复合物在肺内累积的全身递送方案，同时提供对转移性疾病的同时治疗。（1-5年级）。目的3：将目的2中开发的用于特异性递送至肺的β-lap编码的微粒与全身递送（i. p.）HP-β-环糊精-β-lap复合物用于NQ 01特异性肺肿瘤应答的方法。我们将结合联合收割机这些治疗与系统的双香豆素管理正常组织的保护。（1-5年级）。我们已经组建了一个强大的研究团队，具有开发新型药物载体所需的经验，对β-lap和载体在肺中的沉积和递送进行成像，并测试β-lap应该是一种有效的抗NSCLC药物的假设，这是由于NQO 1的肿瘤特异性升高，NQO 1是β-拉帕酮引起的新型钙蛋白酶介导的细胞死亡反应特别需要的生物活化酶。我们将研究双香豆素联合给药可以作为解毒剂的可能性，增加β-lap的抗肿瘤疗效。

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of death by cancer in the U.S. Non-small cell lung cancer (NSCLC) comprises over 75 percent of lung cancers diagnosed. Current chemotherapeutic regimens are not effective against NSCLC, with five-year survival rates hovering at a mere 14 percent. Regimens that exploit cancer-specific targets, specifically in and increase therapeutic indices, should enhance the survival rates of patients. We hypothesize that Beta-lapachone (beta-lap), a drug that selectively kills cancer cells with elevated levels of the two-electron reductase, NAD(P)H:quinone oxidoreductase 1 (NQOI), will be an effective agent for use against NSCLC cells that specifically over-express this bioactivating enzyme. Cell death caused by beta-lap is not dependent on cell cycle status, not dependent on p53, pRb, or caspases, and downstream cell death events are consistent with calpain-mediated apoptosis. More importantly, cell death by beta-lap is dependent on NQO1 expression, where NQO1-deficient cells are resistant to the drug, correction of cells with NQO1 restores lethality, and co-administration of dicumarol (an NQO1 inhibitor) prevents lethality. NQOI is typically elevated 4- to greater than 100-fold in human NSCLC, indicating the use of beta-lap for treatment of this disease. Recent development of novel drug delivery methods make it feasible to administer this drug to determine efficacy against NSCLC in animal models. Three aims will test this hypothesis: Aim 1: Evaluate the role of NQO1 in beta-lap-mediated cell death in NSCLC cells, and develop lab correlates for use in future therapy. (Years 1-3). Aim 2: Develop drug vehicles for beta-lap that either deliver the drug locally to the lung, or utilize systemic delivery schemes that allow accumulation of the vehicle-drug complexes within the lung, while offering simultaneous treatment for metastatic disease. (Years 1-5). Aim 3: Compare beta-lap-encoded microparticles developed in Aim 2 for specific delivery to the lung to systemic delivery (i.p.) of HP-beta-cyclodextrin-beta-lap complexes for NQOl-specific lung tumor responses. We will combine these therapies with systemic dicumarol administration for normal tissue protection. (Years 1-5). We have assembled a strong research team with the needed experience to develop novel drug vehicles, image the deposition and delivery of both beta-lap and the vehicle in the lung, and test the hypothesis that beta-lap should be an efficacious agent against NSCLC due to tumor-specific elevation of NQO 1, a bioactivating enzyme specifically needed for novel calpain-mediated cell death responses elicited by beta-lapachone. We will examine the possibility that co-administration of dicumarol can act as an antidote, increasing the anti-tumor efficacy of beta-lap.