Mechanistic Studies on New Platinum Clinical Agents

这一更新建议的直接意义是研究临床上 基于多(二/三)核基序的相关系列铂基抗癌药物。这项工作源于 从基本原则，即在复方中获得真正不同的抗肿瘤活性概况到 临床使用的药物，需要对结构上不同的DMA加合物进行不同的识别和处理。 这类药物与靶向DMA的相互作用不同于单核顺铂 事实上，与临床上使用的任何破坏DMA的药物不同。的效用的概念证明 这种方法是通过一种名为BBR3464的药物进入人体第二阶段试验而实现的。有了这一进步， 以顺铂为基础的抗肿瘤药物的范式发生了改变。这些药物的化学和生物学特性 认为它们应该被认为是一种全新的DMA修改结构类的代表 抗癌剂。重要的是要了解这些新的相互作用的性质以及它们如何影响 以充分发挥DMA功能的临床潜力。 该提案将研究由多核铂形成的DMA加合物的独特方面 我们实验室中出现的化合物以及形成这些化合物的生物学后果 结构新颖。I期试验显示了癌症患者异常反应的明显模式。 可用顺铂治疗包括对黑色素瘤、胰腺癌和肺癌的反应。客观反应 在第二阶段已经被证实在复发的卵巢癌和非小细胞肺癌中。临床前研究 在BBR3464治疗后，P53突变肿瘤的活性和对P53的最小诱导。它是 该项目的长期目标是了解一种独特的DMA加合物形成模式如何导致 不同的细胞信号或“下游”效应，如蛋白质识别，以及这些事件是否可能 将导致一种真正新的抗肿瘤活性模式。这是该项目的另一个长期目标 将这些化合物的细胞毒性作用置于通向细胞的分子途径的背景下 死亡。 铂类药物是抗癌药物军工厂中最强大的药物之一。澄清 这类新型抗癌剂的作用机理将导致设计出更好、更特异的药物 用于治疗癌症。这些药物将与靶向药物联合使用，以提供更好的 癌症患者的治疗方案。

The immediate significance of this renewal proposal is the study of the mechanism of action of a clinically relevant series of platinum-based anticancer agents based on a poly(di/tri)nuclear motif. The work stems from the fundamental tenet that to obtain a genuinely different profile of antitumor activity in compoariosn to clinically used agents, disparate recognition and processing of structurally distinct DMA adducts is required. The interactions of this class of drugs with target DMA are distinct from the mononuclear-based cisplatin family and, indeed, unlike those of any DMA-damaging agent in clinical use. Proof of concept of the utility of this approach is given by the entry of one agent, BBR3464, to human Phase II trials. With this advance the paradigm of cisplatin-based antitumor agents is altered. The chemical and biological features of these drugs argue that they should be considered representative of an entirely new structural class of DMA-modifying anticancer agents. It is important to understand the nature of these novel interactions and how they affect DMA function in order to exploit their full clinical potential. This proposal will study the unique aspects of the DMA adducts formed by the polynuclear platinum compounds that have emerged from our laboratory and the biological consequences of formation of these novel structures. The Phase I trials demonstrated a clear pattern of responses in cancers not normally treatable with cisplatin including responses in melanoma, pancreatic and lung cancer. Objective responses in Phase II have been verified in relapsed ovarian cancer and non-small cell lung cancer. Pre-clinical studies indicated activity in p53-mutant tumors and a minimal induction of p53 following BBR3464 treatment. It is the long-term goal of this project to understand how a unique pattern of DMA adduct formation may result in different cellular signalling or "downstream" effects such as protein recognition and whether such events may be dictated to lead to a genuinely new pattern of antitumor activity. It is a further long-term goal of this project to place the cytotoxic effects of these compounds into the context of molecular pathways leading to cell death. Platinum drugs are some of the most powerful agents in the cancer drug armamentarium. Elucidating the mechanism of action of this new class of anticancer agents will lead to design of better, more specific drugs for treatment of cancer. The drugs will be used in combination with targetted drugs to provide better treatment regimens for cancer patients.