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; 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。开发成功的治疗药物来治疗激素和化学疗法的难治性晚期转移性帽是一种主要的未满足医疗需求。几项研究表明，前列腺上皮细胞中的氧化应激（OS）可能是导致CAP发生，复发和进展到晚期激素治疗疗法 - 难治性阶段的主要因素之一。因此，减少前列腺中这种高水平的OS可能是开发化学治疗和/或化学预防药物以抗CAP的成功策略。线粒体是超氧化物和其他ROS的主要来源。为了降低细胞ROS水平而不干扰线粒体电子传输链，我们专注于针对线粒体间质空间的自旋诱捕氮氧化物类似物，并使用适当的接头去除超氧化物。这类新药物中的两种铅化合物是CPC-404和CPC-410。两者都阻止了雄激素诱导的人瓶细胞中的OS，并且均表现出对雄激素依赖性和雄激素独立培养的人帽细胞的显着生长抑制作用。基于这些结果，我们建议开发CPC-410或最活跃的类似物（线粒体靶向化合物）作为一种新的化学治疗/化学预防药物用于CAP处理。 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使用单次静脉内（i.v.）或口服（p.o）在初步的药代动力学研究中使用标准LC-MS方案给药，3），以确定在药物减少药物治疗的氧化应激减少药物治疗药物毒性剂量增加的药物学研究中，最有效的铅药物候选剂量。在静脉注射后，将确定动物前列腺上皮细胞中上皮细胞中的体内氧化应激（HET）染料氧化。在牺牲和收获前列腺前一小时注射HET，4）测试铅化合物在抑制人帽细胞系雄激素依赖性LNCAP和雄激素独立PC-3异摩口的裸鼠中的化学治疗功效，并在裸小鼠中使用效率，以便与该效率进行效率，以便与DoceTaxel的效率进行比较，以便与DOCETAXEL的效率进行比较，以使其与DOCETAXEL的效率相比，我们的效率是我们的效率。铅候选者对自发小鼠前列腺肿瘤的发生和生长的化学预防疗效在小鼠前列腺（Tramp）动物的转基因腺癌​​中的发生和生长，并将其治疗效率与Bicalutamide（Casodex）的疗效进行比较。 公共卫生相关性：晚期雄激素消耗疗法（ADT） - 耐药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依赖雄激素的肿瘤，并通过手术或放射疗法进行治疗，然后进行雄激素消耗治疗。不幸的是，这些患者中的大多数患有晚期激素 - 难治性转移性前列腺肿瘤，这些肿瘤对任何当前的常规癌症疗法反应较差。因此，有很强的未满足医学需要开发新的治疗药物，以防止前列腺肿瘤从雄激素依赖性到雄激素独立态以及治疗晚期转移性雄激素独立肿瘤的发生，复发和/或进展。我们发现，某些线粒体指导的抗氧化药物对雄激素依赖性和雄激素独立的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，这些候选药物受动物的耐受性。在这里，我们提出了I期SBIR前临床研究，以鉴定铅药物候选药物并发展为临床上有用的抗验证癌药物。