Mitochondria Targeted Anti-oxidant for Treatment of Prostate Cancer

线粒体靶向抗氧化剂治疗前列腺癌

• 批准号: 7483307
• 负责人: Hirak S. Basu
• 金额: $ 10.96万
• 依托单位: COLBY PHARMACEUTICAL COMPANY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483307
• 关键词: Adenocarcinoma; Androgen Therapy; Androgens; Animals; Antineoplastic Agents; Antioxidants; Bicalutamide; Biological Assay; Cancer Etiology; Cations; Cell Line; Cells; Cessation of life; Chemopreventive Agent; Class; Clinical Treatment; Clinical Trials; Collaborations; Diagnosis; Disease; Dose; Drug Formulations; Drug Kinetics; Drug usage; Dyes; Electron Transport; Electrons; Epithelial Cells; Epithelium; Exhibits; Fluorescence; Generations; Growth; Half-Life; Harvest; Hormones; Hour; Human; Hydrogen Peroxide; Injection of therapeutic agent; Intravenous; LNCaP; Laboratories; Lead; Legal patent; Malignant Neoplasms; Malignant neoplasm of prostate; Maximum Tolerated Dose; Medical; Metastatic Prostate Cancer; Mitochondria; Mitochondrial Matrix; Mus; Nude Mice; Operative Surgical Procedures; Oral; Oxidative Stress; Parkinson Disease; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Play; Primary Neoplasm; Procedures; Production; Prostate; Prostatic Neoplasms; Protocols documentation; Public Health; Publishing; Quinones; Radiation therapy; Reactive Oxygen Species; Recurrence; Refractory; Research Personnel; Resistance; Role; Route; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Source; Spin Trapping; Staging; Superoxides; Testing; Therapeutic; Tissues; Toxic effect; Transgenic Organisms; Transport Process; Treatment Efficacy; Ubiquinone; Universities; Wisconsin; Work; Xenograft procedure; analog; androgen independent prostate cancer; base; benzoquinone; cancer therapy; chemotherapeutic agent; chemotherapy; college; cytotoxic; design; docetaxel; free radical oxygen; hormone therapy; hydroethidine; in vivo; interstitial; men; nitroxyl; novel therapeutics; oxidation; preclinical study; prevent; professor; tempol; therapy resistant; tumor

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is among the leading causes of cancer deaths among US men. Developing a successful therapeutic drug to treat hormone- and chemo-therapy refractory advanced metastatic CaP is a major unmet medical need. Several studies have shown that the oxidative stress (OS) in prostate epithelial cells is likely one of the major contributors to CaP occurrence, recurrence and progression to advanced hormone therapy-refractory stage. Therefore, reducing this high level of OS in the prostate gland can be a successful strategy for developing chemotherapeutic and/or chemopreventive drugs for use against CaP. The mitochondria are a major source of superoxide and other ROS. In order to reduce the cellular ROS levels without interfering with the mitochondrial electron transport chain, we focused on targeting spin-trapping nitroxide analogs at the mitochondrial interstitial space with appropriate linker in order to remove the superoxide. Two of our lead compounds in this new class of drugs are CPC-404 and CPC-410. Both blocked androgen-induced OS in human CaP cells and both exhibited marked growth inhibitory effects against androgen-dependent as well as androgen-independent cultured human CaP cells. Based on these results, we propose to develop CPC-410 or its most active analog (a mitochondria targeted compound) as a new chemotherapeutic/chemopreventive drug for CaP treatment. Our Specific Aims are: 1) to design, synthesize and test CPC-410 and its analogs with anti-oxidant activity against mitochondrial superoxide production and to select the most active analog for maximum anti-proliferative activity against human CaP cells and the least cytotoxic effect against the immortalized normal human prostate epithelial cells (HPEC) in culture, using published protocols, 2) to standardize an effective formulation and route of administration using single intravenous (i.v.) or oral (p.o) administration of the lead drug candidate in preliminary pharmacokinetic studies using a standardized LC-MS protocol, 3) To determine the most efficacious dose of the lead drug candidate in pharmacodynamic studies for reduction of oxidative stress in animal prostate tissues treated with increasing drug doses. The in vivo oxidative stress in animal prostate epithelial cells will be determined following a standardized fluorescence assay for hydroethidine (HEt) dye oxidation after i.v. injection of HEt one hour before sacrifice and harvesting of the prostate gland, 4) To test the chemotherapeutic efficacy of the lead compound in inhibiting the growth of human CaP cell lines androgen-dependent LNCaP and androgen- independent PC-3 xenografts in nude mice and to compare its efficacy with that of docetaxel following published procedures used routinely in our laboratory, 5) To test the chemopreventive efficacy of the lead candidate on the occurrence and growth of spontaneous mouse prostate tumors in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) animals and to compare its therapeutic efficacy with that of bicalutamide (Casodex). PUBLIC HEALTH RELEVANCE: Advanced Androgen Depletion Therapy (ADT)-resistant metastatic prostate cancer is the second leading cause of cancer deaths among US men. Many prostate cancers are detected as androgen-dependent tumors and are treated by surgery or radiotherapy followed by androgen depletion therapy. Unfortunately, a majority of these patients return with advanced hormone-refractory metastatic prostate tumors that respond poorly to any current conventional cancer therapy. Thus, there is a strong unmet medical need to develop novel therapeutic drugs to prevent the occurrence, recurrence and/or progression of prostate tumors from androgen-dependent to androgen-independent states as well as to treat advanced metastatic androgen- independent tumors. We discovered that certain mitochondria-directed anti-oxidant drugs exhibit very strong anti-proliferative effects against both androgen-dependent and androgen-independent prostate cancer. In preliminary preclinical studies, these drug candidates are well-tolerated by animals. Here, we propose Phase I SBIR pre- clinical studies necessary to identify the lead drug candidate and develop as a clinically useful anti-prostate cancer drug.

描述（由申请人提供）：前列腺癌 (CaP) 是美国男性癌症死亡的主要原因之一。开发一种成功的治疗药物来治疗激素和化疗难治性晚期转移性 CaP 是一项未满足的重大医疗需求。多项研究表明，前列腺上皮细胞中的氧化应激（OS）可能是导致 CaP 发生、复发和进展至晚期激素治疗难治期的主要原因之一。因此，降低前列腺中这种高水平的 OS 可能是开发用于对抗 CaP 的化疗和/或化学预防药物的成功策略。线粒体是超氧化物和其他活性氧的主要来源。为了在不干扰线粒体电子传递链的情况下降低细胞ROS水平，我们专注于使用适当的接头在线粒体间隙中靶向自旋捕获硝基氧类似物，以去除超氧化物。我们此类新药物中的两种先导化合物是 CPC-404 和 CPC-410。两者均能阻断人 CaP 细胞中雄激素诱导的 OS，并且对雄激素依赖性和雄激素非依赖性培养的人 CaP 细胞均表现出明显的生长抑制作用。基于这些结果，我们建议开发 CPC-410 或其最活跃的类似物（线粒体靶向化合物）作为用于 CaP 治疗的新型化疗/化学预防药物。我们的具体目标是：1) 使用已公布的实验方案，设计、合成和测试 CPC-410 及其类似物对线粒体超氧化物产生的抗氧化活性，并选择最活跃的类似物，对人 CaP 细胞具有最大的抗增殖活性，对培养中的永生化正常人前列腺上皮细胞 (HPEC) 具有最小的细胞毒性作用，2) 标准化有效的配方和途径 使用标准化 LC-MS 方案，在初步药代动力学研究中使用单次静脉内 (i.v.) 或口服 (p.o) 施用主要候选药物的给药方法，3) 确定药效学研究中主要候选药物的最有效剂量，以减少经增加药物剂量治疗的动物前列腺组织中的氧化应激。动物前列腺上皮细胞的体内氧化应激将通过静脉注射后氢乙啶 (HEt) 染料氧化的标准化荧光测定来确定。在处死和收获前列腺前一小时注射 HEt，4) 测试先导化合物在裸鼠中抑制人 CaP 细胞系雄激素依赖性 LNCaP 和雄激素非依赖性 PC-3 异种移植物生长的化疗功效，并按照我们实验室常规使用的已公布程序将其功效与多西紫杉醇的功效进行比较，5) 测试 主要候选药物对转基因小鼠前列腺腺癌 (TRAMP) 动物中自发性小鼠前列腺肿瘤的发生和生长的化学预防功效，并将其与比卡鲁胺 (Casodex) 的治疗效果进行比较。 公共健康相关性：晚期雄激素耗竭疗法 (ADT) 耐药的转移性前列腺癌是美国男性癌症死亡的第二大原因。许多前列腺癌被检测为雄激素依赖性肿瘤，并通过手术或放疗以及随后的雄激素耗竭疗法进行治疗。不幸的是，这些患者中的大多数返回时患有晚期激素难治性转移性前列腺肿瘤，这些肿瘤对任何当前的传统癌症治疗反应不佳。因此，存在强烈的未满足的医学需求，即开发新的治疗药物以预防前列腺肿瘤从雄激素依赖性状态向雄激素非依赖性状态的发生、复发和/或进展以及治疗晚期转移性雄激素非依赖性肿瘤。我们发现某些线粒体定向抗氧化药物对雄激素依赖性和雄激素非依赖性前列腺癌表现出非常强的抗增殖作用。在初步的临床前研究中，这些候选药物对动物具有良好的耐受性。在这里，我们建议进行 I 期 SBIR 临床前研究，以确定主要候选药物并开发为临床上有用的抗前列腺癌药物。