Use of Beta-Lapachone for Lung Cancer Chemotherapy

描述(由申请人提供)： 在美国，肺癌是主要的癌症死亡原因。非小细胞肺癌(NSCLC)占确诊肺癌的75%以上。目前的化疗方案对非小细胞肺癌无效，五年存活率仅徘徊在14%。利用癌症特异性靶点的方案，特别是在提高治疗指数方面，应该会提高患者的存活率。我们假设，β-拉帕酮(β-LAP)，一种选择性地杀死两电子还原酶NAD(P)H：苯醌氧化还原酶1(NQOI)水平升高的癌细胞的药物，将是一种有效的药物，用于对抗NSCLC细胞特异性地过度表达这种生物激活酶。β-LAP引起的细胞死亡不依赖于细胞周期状态，也不依赖于P53、pRB或caspase，下游的细胞死亡事件与Calain介导的细胞凋亡是一致的。更重要的是，β-LAP导致的细胞死亡依赖于NQO1的表达，其中NQO1缺陷的细胞对药物具有抗药性，纠正NQO1的细胞可以恢复致死性，联合使用Dicumarol(一种NQO1抑制剂)可以防止致死性。在人类非小细胞肺癌患者中，NQOI通常升高4-到100倍以上，这表明使用Beta-LAP治疗这种疾病。近年来，新的给药方法的发展使得在动物模型中应用该药物来确定对非小细胞肺癌的疗效是可行的。三个目标将检验这一假设： 目的1：探讨NQO1在β-LAP介导的非小细胞肺癌细胞死亡中的作用。 实验室的相关研究可用于未来的治疗。(1-3年级)。目标2：开发用于Beta-LAP的药物载体，既可以将药物局部输送到肺内，也可以利用全身给药方案，允许载体-药物复合体在肺内积累，同时提供对转移疾病的治疗。(1-5年级)。目标3：比较目标2中开发的用于肺部特定给药的β-LAP编码微粒与全身给药(I.P.)Hp-β-环糊精-β-LAP复合体对NQO1特异性肺肿瘤反应的研究。我们将结合这些疗法和全身给药来保护正常的组织。(1-5年级)。我们已经组建了一个强大的研究团队，拥有开发新型药物载体所需的经验，成像β-LAP和载体在肺中的沉积和递送，并测试由于肿瘤特异性的NQO 1升高，β-LAP应该是对抗NSCLC的有效药物的假设，NQO 1是一种生物活性酶，特别是由β-雷帕酮引发的新型钙蛋白介导的细胞死亡反应所需的生物活化酶。我们将研究联合应用双库马罗尔作为解毒剂的可能性，从而增加β-LAP的抗肿瘤效果。

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.