Mechanistic Studies on New Platinum Clinical Agents

新型铂类临床药物的作用机制研究

• 批准号: 7476038
• 负责人: NICHOLAS P FARRELL
• 金额: $ 28.14万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476038
• 关键词: Affect; Affinity; Affinity Labels; Antineoplastic Agents; BBR 3464; Binding; Biological; Cancer Patient; Cell Death; Charge; Chemical Structure; Chemicals; Cisplatin; Class; Clinical; Combination Chemotherapy; Complex; Coupled; Cytosol; DNA; DNA Adducts; DNA Binding; DNA Interstrand Crosslinking; DNA Repair; Drug Delivery Systems; Drug Kinetics; Event; Family; Fractionation; Frequencies; Glioma; Goals; Human; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Measures; Membrane Potentials; Minor Groove; Mitochondria; Modeling; Molecular; Molecular Conformation; Molecular Structure; Mononuclear; Nature; Non-Small-Cell Lung Carcinoma; Nuclear; Nucleotide Excision Repair; Pancreas; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phospholipids; Platinum; Platinum Compounds; Polyamines; Polymers; Process; Property; Proteins; RNA; Range; Relapse; Series; Signal Pathway; Signal Transduction; Specificity; Structure; TP53 gene; Techniques; Tissues; Treatment Protocols; Vertebral column; Work; adduct; affinity labeling; analog; antitumor agent; base; cancer therapy; clinically relevant; concept; crosslink; cytotoxic; cytotoxicity; design; inorganic phosphate; intercalation; melanoma; mutant; novel; preclinical study; protein activation; repaired; response; stem; tumor; uptake

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.

这一更新建议的直接意义是研究临床上一种 基于聚（二/三）核基序的相关系列铂基抗癌剂。作品Stem 从基本的原则，即获得真正不同的抗肿瘤活性的组合物， 在临床上使用的试剂中，需要对结构上不同的DMA加合物进行不同的识别和处理。 此类药物与靶点DMA的相互作用与基于单核的顺铂不同 事实上，与临床使用的任何DMA损伤剂不同。实用性的概念证明 这种方法通过一种药剂BBR 3464进入人体II期试验而得到。随着这一进步， 基于顺铂的抗肿瘤剂的范例被改变。这些药物的化学和生物学特征 他们认为，他们应该被视为一个全新的结构类DMA修改的代表 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 DMA功能，以充分发挥其临床潜力。 该提案将研究由多核铂形成的DMA加合物的独特方面 我们的实验室中出现的化合物以及这些化合物形成的生物学后果 新颖的结构。I期试验表明，在癌症中， 可用顺铂治疗，包括在黑色素瘤、胰腺癌和肺癌中的反应。客观缓解 在II期中，已在复发性卵巢癌和非小细胞肺癌中得到验证。临床前研究 表明在p53突变肿瘤中的活性和BBR 3464处理后对p53的最小诱导。是 本项目的长期目标是了解DMA加合物形成的独特模式如何导致 不同的细胞信号传导或“下游”效应，如蛋白质识别，以及这些事件是否可以 将导致一种真正的新型抗肿瘤活性。这是该项目的一个更长远的目标， 为了将这些化合物的细胞毒性作用置于导致细胞凋亡的分子途径的背景中， 死亡 铂类药物是抗癌药物中最强大的药物之一。阐明 这类新的抗癌药物的作用机制将导致设计出更好、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， 癌症患者的治疗方案。

项目成果

Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.

• DOI: 10.1021/jm8013234
• 发表时间: 2009-02-26
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Mendoza-Ferri MG;Hartinger CG;Mendoza MA;Groessl M;Egger AE;Eichinger RE;Mangrum JB;Farrell NP;Maruszak M;Bednarski PJ;Klein F;Jakupec MA;Nazarov AA;Severin K;Keppler BK
• 通讯作者: Keppler BK