MDA-7/IL-24 and free radicals in renal cancer therapy

MDA-7/IL-24 和自由基在肾癌治疗中的作用

• 批准号: 7469401
• 负责人: PAUL DENT
• 金额: $ 27.9万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469401
• 关键词: 1-Phosphatidylinositol 3-Kinase; 1q32; Apoptosis; Arsenic Trioxide; Cell Cycle Arrest; Cell Death; Cell Proliferation; Cell Survival; Cells; Chimeric Proteins; Chromosomes; Combined Modality Therapy; Complex; Conditioned Culture Media; DNA-dependent protein kinase; Disease; Dose; Enhancers; Epithelial Cells; Excision; Fascia; Fenretinide; Free Radicals; Growth; Hepatocyte; Human Genome; Immunotherapy; In Vitro; Infusion procedures; Interleukin-10; JUN gene; Kidney; Location; MAP Kinase Gene; MAPK11 gene; MAPK14 gene; MAPK8 gene; Malignant neoplasm of kidney; Mediating; Mitochondria; Mitogen-Activated Protein Kinase 3; Modality; N-terminal; Nephrectomy; Operative Surgical Procedures; Pathway interactions; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Phosphatidylinositols; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Phosphotransferases; Play; Proteins; Proto-Oncogene Proteins c-akt; Radiation therapy; Range; Reactive Oxygen Species; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; STAT1 gene; STAT3 gene; Signal Pathway; Signal Transduction; Stress; Systemic Therapy; Therapeutic; Toxic effect; Virus; base; cancer therapy; cell growth; cell killing; cell transformation; cell type; chemotherapy; cytokine; cytotoxic; eIF-2 Kinase; extracellular; inhibitor/antagonist; interleukin 20; interleukin-19; kidney cell; killings; kinase inhibitor; member; mutant; neoplastic cell; retinamide; stress-activated protein kinase 1; tumor; tumor growth

DESCRIPTION (provided by applicant): Renal Cell Carcinoma (RCC) is among the most lethal and difficult tumors to treat, particularly when disease has spread beyond the kidney and into the surrounding fascia; even intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on patient survival. There is a major need for alternative therapeutic modalities. Expression of MDA-7/IL-24 in many different tumor cell types causes growth arrest and apoptosis whereas in non-transformed cells it alters neither cell growth nor cell survival. Previous studies have shown that MDA-7 administered either as a virus (Ad.mda-7), as a purified fusion protein (GST-MDA-7), or in conditioned media, suppressed the growth of tumor cells. In RCC we found that low concentrations of MDA-7 (0.5-1.5 nM) suppressed growth without killing cells whereas higher levels of MDA-7 (> 20 nM) suppressed growth and enhanced cell death. Low levels of MDA-7 enhanced the sensitivity of RCCs to several agents that generate free radicals. The anti-proliferative and cytotoxic effects of MDA-7 and free radicals were not observed in primary renal cells. The mechanisms by which MDA-7 inhibits RCC proliferation and interacts with free radicals to kill RCCs are not fully understood. Specific aim 1 will determine whether GST-MDA-7, in a dose-dependent fashion, causes increasing amounts of p38 MAPK activation and JNK1/2 activation, in RCCs, whose signaling is believed to be responsible for cytokine-induced apoptosis at high (> 30 nM) GST-MDA-7 concentrations. Additionally, we will prove or refute whether [arsenic trioxide (As2O3) and N-(4-hydroxyphenyl) retinamide (4-HPR)], agents that generate reactive oxygen species, enhance the ability of low GST-MDA-7 concentrations (0.5-1.5 nM) to cause prolonged activation of the p38 and JNK1/2 pathways. Specific aim 2 will determine the mechanisms by which combined treatment of RCCs with PI3 kinase and MEK1/2 inhibitors enhance cell killing by purified MDA-7 protein. Additionally, we will prove or refute whether [arsenic trioxide (As2O3) and N-(4-hydroxyphenyl) retinamide (4-HPR)], agents that generate reactive oxygen species, enhance the lethality of low GST-MDA-7 concentrations by causing inactivation of ERK1/2. Specific aim 3 will determine whether infusion of Ad.mda-7 or MDA-7 protein, into a pre-existing tumor, reduces RCC growth and enhances tumor sensitivity to As2O3 and 4-HPR.

描述（由申请人提供）：肾细胞癌（RCC）是最致命和最难治疗的肿瘤之一，特别是当疾病已经扩散到肾脏以外并进入周围筋膜时;即使是放射性和化学疗法的强化组合也不能治愈，并且对患者生存仅产生适度的影响。对替代治疗方式的需求很大。MDA-7/IL-24在许多不同肿瘤细胞类型中的表达引起生长停滞和凋亡，而在非转化细胞中，它既不改变细胞生长也不改变细胞存活。以前的研究表明，MDA-7无论是作为病毒（Ad.mda-7），作为纯化的融合蛋白（GST-MDA-7），或在条件培养基中，抑制肿瘤细胞的生长。在RCC中，我们发现低浓度的MDA-7（0.5-1.5 nM）抑制生长而不杀死细胞，而较高水平的MDA-7（> 20 nM）抑制生长并增强细胞死亡。低水平的MDA-7增强了RCC对几种产生自由基的药物的敏感性。在原代肾细胞中未观察到MDA-7和自由基的抗增殖和细胞毒性作用。MDA-7抑制RCC增殖并与自由基相互作用杀死RCC的机制尚未完全了解。具体目标1将确定GST-MDA-7是否以剂量依赖性方式在RCC中引起增加量的p38 MAPK活化和JNK 1/2活化，其信号传导被认为是在高（> 30 nM）GST-MDA-7浓度下马槟榔碱诱导的细胞凋亡的原因。此外，我们将证明或反驳是否[三氧化二砷（As 2 O3）和N-（4-羟基苯基）维甲酰胺（4-HPR）]，产生活性氧的药物，增强低GST-MDA-7浓度（0.5-1.5 nM）引起p38和JNK 1/2通路激活延长的能力。具体目标2将确定与PI 3激酶和MEK 1/2抑制剂联合治疗RCC增强纯化的MDA-7蛋白的细胞杀伤的机制。此外，我们将证明或反驳是否[三氧化二砷（As 2 O3）和N-（4-羟基苯基）视黄酰胺（4-HPR）]，产生活性氧的药物，通过引起ERK 1/2失活增强低浓度GST-MDA-7的致死性。具体目标3将确定向预先存在的肿瘤中输注Ad.mda-7或MDA-7蛋白是否减少RCC生长并增强肿瘤对As 2 O3和4-HPR的敏感性。