Redox-Active Ruthenium Complexes for Cancer Treatment

用于癌症治疗的氧化还原活性钌配合物

基本信息

批准号：
7778988
负责人：
FREDERICK M MACDONNELL
金额：
$ 21.38万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778988
关键词：
Acute Address Affect Animal Model Animals Antineoplastic Agents Apoptosis Behavior Binding Biochemical Pathway Biological Biological Assay Brain Cancer cell line Cancerous Carbon Caspase Cell Culture Techniques Cell Line Cell membrane Cells Chemical Actions Chemicals Chemotherapy-Oncologic Procedure Cisplatin Cleaved cell Complex Cultured Cells DNA DNA Binding DNA Damage Data Deoxyribose Drug usage Electron Spin Resonance Spectroscopy Future Gene Targeting Genes Glutathione Grant Heart Human Hypoxia Hypoxia Inducible Factor Implant In Situ In Vitro Intercalating Agents Intestines Kidney Lead Ligands Liver Lung Mediating Modeling Mono-S Mus Non-Small-Cell Lung Carcinoma Normal Cell Nuclear Nude Mice Oxidation-Reduction Oxygen measurement, partial pressure, arterial Pathway interactions Pharmaceutical Preparations Poison Process Proto-Oncogenes Reaction Reducing Agents Ruthenium Site Specificity Spleen Staining method Stains Stress Structure Structure-Activity Relationship TdT-Mediated dUTP Nick End Labeling Assay Techniques Testing Time Tissues Toxic effect Transition Elements Type I DNA Topoisomerases VEGFA gene Vascular Endothelial Growth Factors Work analog antitumor agent base cancer cell cancer therapy cell type cytotoxic cytotoxicity drug candidate in vivo interest killings lactate dehydrogenase A melanoma metal complex mouse model neoplastic cell novel public health relevance stereochemistry success tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The tremendous success of cisplatin, cis-[Pt(NH3)2Cl2], in human cancer chemotherapy has led to interest in the potential for complexes of another transition metal, Ru (II), to function as an anti-cancer agents. We have developed a class of ruthenium complexes which incorporate a redox-active intercalating ligand denoted tatpp. These ruthenium-tatpp complexes have been shown to tightly bind DNA and to cause DNA cleavage under conditions of low oxygen tension (hypoxia) and in the presence of common cellular reductants, e.g. glutathione. In our initial grant period, we have shown that mice implanted with either mouse melanoma (B16) or nude mice implanted with human non-small cell lung carcinoma (H358) tumor cells show arrested tumor growth and extended lifetimes when treated with two specific ruthenium-tatpp complexes. We have also shown that these complexes are cytotoxic towards a broad range of cancer cell lines but are considerably (~10 fold difference) less toxic to normal cells. Animal acute-toxicity studies show that chiral versions of these complexes are not appreciably toxic and can be safely be used and drugs. Thus all of our initial data suggests that this class of compounds may have potential an future chemotherapeutic drugs for cancer treatment. In our initial grant period, we established a number of structure-activity relationships and established that only complexes containing redox-active bridging ligands were promising drug candidates. In this proposal, we aim to prepare a number of new complexes in which both the reduction potential of the bridging ligand and the other anciallary ligands are varied to further delineate the structure-activity relationships for this class of compounds. The new complexes will be screened for DNA binding, DNA cleavage and cytotoxicty towards two cancer cells lines. Promising candidates will be further examined in animal models. In addition to establishing structure-activity relationships, we propose to examine the mechanism of DNA cleavage in detail using combination of EPR techniques and DNA product analysis studies. The unusual behavior under hypoxic conditions suggests a novel mechanism of action. We also will examine the detailed mechanism of chemical action for the DNA cleavage reaction and examine the biological pathways affected by drug treatment. In particular, we will examine the affect of these complexes on factors, e.g. HIF-1/2, VEGF, LDH-A, associated with hypoxic stress in both cells and in animals. PUBLIC HEALTH RELEVANCE: We are developing a class of potential anti-cancer drugs based on ruthenium metal complexes in which one ligand is redox-active under common biological conditions. These compounds are able to arrest tumor growth in mice and show high specificity for killing tumor cells over normal cells. These compounds bind and cleave DNA and recently we have shown that they do so better under conditions of low oxygen tension (hypoxia). This is promising because tumor cells under hypoxic stress are one of the most difficult subpopulations of cancer cells to treat and few compounds show better activity under hypoxic conditions over normal conditions.

描述（由申请人提供）：在人类癌症化学疗法中顺铂，顺铂，顺铂（pt（nh3）2cl2）的巨大成功，引起了对另一种过渡金属RU（II）的复合物的潜力，从而成为抗癌药物的潜力。我们已经开发了一类钌配合物，其中包含氧化还原活性的插入配体表示的TATPP。这些ruthenium-TATPP复合物已显示出在低氧张力（缺氧）的条件下以及存在常见的细胞还原剂（例如，例如，例如。谷胱甘肽。在我们的最初赠款期间，我们已经表明，植入小鼠黑色素瘤（B16）或植入人类非小细胞肺癌（H358）肿瘤细胞的小鼠肿瘤细胞显示肿瘤的生长和延长的寿命，当时用两种特定的ruthenium-Tatpp复合物治疗。我们还表明，这些复合物对广泛的癌细胞系具有细胞毒性，但对正常细胞的毒性较小（约10倍差）。动物急性毒性研究表明，这些复合物的手性版本不是明显的毒性，可以安全地使用和药物。因此，我们所有的初始数据都表明，这类化合物可能具有未来的化学治疗药物来进行癌症治疗。在我们的最初赠款期间，我们建立了许多结构活性关系，并确定只有含有氧化还原活性桥接配体的复合物是有希望的候选药物。在此提案中，我们旨在准备许多新的复合物，在这些复合物中，桥接配体的还原电位和其他固有配体都会变化，以进一步描述此类化合物的结构活性关系。新的复合物将筛选以与两个癌细胞系的DNA结合，DNA裂解和细胞毒性。在动物模型中将进一步研究有希望的候选人。除了建立结构活性关系外，我们还建议使用EPR技术和DNA乘积分析研究的组合详细检查DNA裂解的机制。低氧条件下的异常行为表明了一种新型的作用机理。我们还将检查DNA裂解反应的化学作用的详细机制，并检查受药物治疗影响的生物学途径。特别是，我们将研究这些复合物对因素的影响，例如HIF-1/2，VEGF，LDH-A，与动物和动物中的低氧应激相关。公共卫生相关性：我们正在基于芳族金属复合物开发一类潜在的抗癌药物，其中一种配体在常见的生物学条件下具有氧化还原活性。这些化合物能够阻止小鼠的肿瘤生长，并显示出高特异性，可在正常细胞上杀死肿瘤细胞。这些化合物结合并裂解DNA，最近我们表明它们在低氧张力（低氧）条件下做得更好。这是有希望的，因为低氧应激下的肿瘤细胞是癌细胞最困难的亚群之一，而在正常条件下，在低氧条件下，很少有化合物在低氧条件下表现出更好的活性。