Redox-Active Ruthenium Complexes for Cancer Treatment

描述（由申请人提供）：顺铂（cis-[Pt(NH3)2Cl2]）在人类癌症化疗中的巨大成功，引起了人们对另一种过渡金属Ru （II）配合物作为抗癌药物的潜力的兴趣。我们已经开发了一类钌配合物，它包含一个氧化还原活性的插入配体，标记为tatpp。这些钌-tatpp复合物已被证明在低氧张力（缺氧）和普通细胞还原剂（如谷胱甘肽）存在的条件下紧密结合DNA并引起DNA分裂。在我们最初的资助阶段，我们已经证明，植入小鼠黑色素瘤（B16）的小鼠或植入人类非小细胞肺癌（H358）肿瘤细胞的裸鼠，在接受两种特定的钌-tatpp复合物治疗时，肿瘤生长被抑制，寿命延长。我们还表明，这些复合物对多种癌细胞系具有细胞毒性，但对正常细胞的毒性要小得多（相差约10倍）。动物急性毒性研究表明，这些复合物的手性版本没有明显的毒性，可以安全地与药物一起使用。因此，我们所有的初步数据表明，这类化合物可能有潜力成为未来癌症治疗的化疗药物。在我们最初的授权期间，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配合物才是有希望的候选药物。在本提案中，我们的目标是制备一些新的配合物，其中桥接配体和其他配体的还原电位都是不同的，以进一步描述这类化合物的结构-活性关系。新的复合物将被筛选DNA结合，DNA切割和对两种癌细胞系的细胞毒性。有希望的候选药物将在动物模型中进一步研究。除了建立结构-活性关系外，我们还建议结合EPR技术和DNA产物分析研究来详细研究DNA切割的机制。缺氧条件下的异常行为提示了一种新的作用机制。我们还将研究DNA切割反应的化学作用的详细机制，并研究受药物治疗影响的生物学途径。特别是，我们将检查这些复合物对因子的影响，如HIF-1/2， VEGF, ldl - a，在细胞和动物中与缺氧应激相关。

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.