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: 8035451
• 负责人: NICHOLAS P FARRELL
• 金额: $ 30.32万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035451
• 关键词: Affect; Affinity; Affinity Labels; Antineoplastic Agents; Binding; Biological; Cancer Patient; Cell Death; Charge; Chemical Structure; Chemicals; Cisplatin; Clinical; Combination Drug Therapy; Complex; Coupled; DNA; DNA Adduction; DNA Adducts; DNA Binding; DNA Binding Agent; DNA Damage; DNA Interstrand Crosslinking; DNA Repair; Drug Delivery Systems; Drug Kinetics; Event; Family; Frequencies; Goals; Health; Human; Label; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Measures; Membrane Potentials; Methods; Minor Groove; Molecular; Molecular Conformation; Molecular Structure; Mononuclear; Nature; Non-Small-Cell Lung Carcinoma; Nuclear; Nucleotide Excision Repair; Pathway interactions; Pattern; Pattern Recognition; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Platinum; Platinum Compounds; Polyamines; Polymers; Process; Property; Proteins; RNA; Relapse; Series; Signal Pathway; Signal Transduction; Specificity; Structure; Techniques; Tissues; Treatment Protocols; Vertebral column; Work; adduct; affinity labeling; analog; antitumor agent; base; cancer cell; cancer therapy; clinically relevant; crosslink; cytotoxic; cytotoxicity; design; inorganic phosphate; intercalation; melanoma; mutant; neoplastic cell; novel; preclinical study; repaired; response; stem; tumor; uptake

DESCRIPTION (provided by applicant): The immediate significance of this revised 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 comparison to clinically used agents, a different pattern of recognition and processing of structurally distinct DNA adducts is required. The interactions of this class of drugs with target DNA are distinct from the mononuclear-based cisplatin family and, indeed, unlike those of any DNA-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 DNA- modifying anticancer agents. It is important to understand the nature of these novel interactions and how they affect DNA function in order to exploit their full clinical potential. This proposal will study the unique aspects of the DNA 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 DNA adduct formation may result in different cellular signaling 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 targeted drugs to provide better treatment regimens for cancer patients. PUBLIC HEALTH RELEVANCE: 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 targeted drugs to provide better treatment regimens for cancer patients.

描述（由申请人提供）：该修订后的更新提案的直接意义是研究基于多（二/三）核基序的临床相关系列铂类抗癌药物的作用机制。这项工作源于这样一个基本原则：与临床使用的药物相比，为了获得真正不同的抗肿瘤活性，需要对结构不同的 DNA 加合物采用不同的识别和加工模式。这类药物与靶 DNA 的相互作用不同于基于单核的顺铂家族，而且实际上也不同于临床使用的任何 DNA 损伤剂。一种药物 BBR3464 进入人体 II 期试验，证明了这种方法的实用性。随着这一进展，基于顺铂的抗肿瘤药物的范例发生了改变。这些药物的化学和生物学特征表明它们应该被视为代表一类全新结构的 DNA 修饰抗癌药物。了解这些新颖相互作用的本质以及它们如何影响 DNA 功能以充分发挥其临床潜力非常重要。该提案将研究我们实验室出现的多核铂化合物形成的 DNA 加合物的独特之处以及这些新结构形成的生物学后果。 I 期试验证明了顺铂通常无法治疗的癌症的明显反应模式，包括黑色素瘤、胰腺癌和肺癌的反应。 II 期的客观反应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，BBR3464 治疗后在 p53 突变肿瘤中具有活性，并且 p53 的诱导程度最低。该项目的长期目标是了解 DNA 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（例如蛋白质识别），以及这些事件是否可能导致真正新的抗肿瘤活性模式。该项目的另一个长期目标是将这些化合物的细胞毒性作用置于导致细胞死亡的分子途径的背景下。铂类药物是抗癌药物中最强大的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更特异的癌症治疗药物。该药物将与靶向药物联合使用，为癌症患者提供更好的治疗方案。公众健康相关性：铂类药物是抗癌药物中最强大的药物之一。阐明这类新型抗癌药物的作用机制将有助于设计出更好、更特异的癌症治疗药物。该药物将与靶向药物联合使用，为癌症患者提供更好的治疗方案。