Mechanistic Studies on New Platinum Clinical Agents
新型铂类临床药物的作用机制研究
基本信息
- 批准号:8235958
- 负责人:
- 金额:$ 30.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-09-30 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAffinity LabelsAntineoplastic AgentsBindingBiologicalCancer PatientCell DeathChargeChemical StructureChemicalsCisplatinClinicalCombination Drug TherapyComplexCoupledDNADNA AdductionDNA AdductsDNA BindingDNA Binding AgentDNA DamageDNA Interstrand CrosslinkingDNA RepairDrug Delivery SystemsDrug KineticsEventFamilyFrequenciesGoalsHumanLabelLaboratoriesLeadLinkMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMalignant neoplasm of pancreasMeasuresMembrane PotentialsMethodsMinor GrooveMolecularMolecular ConformationMolecular StructureMononuclearNatureNon-Small-Cell Lung CarcinomaNuclearNucleotide Excision RepairPathway interactionsPatternPattern RecognitionPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPlatinumPlatinum CompoundsPolyaminesPolymersProcessPropertyProteinsRNARelapseSeriesSignal PathwaySignal TransductionSpecificityStructureTechniquesTissuesTreatment ProtocolsVertebral columnWorkadductaffinity labelinganalogantitumor agentbasecancer cellcancer therapyclinically relevantcrosslinkcytotoxiccytotoxicitydesigninorganic phosphateintercalationmelanomamutantneoplastic cellnovelpreclinical studyrepairedresponsestemtumoruptake
项目摘要
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 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. 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.
这项修订后的更新提案的直接意义是研究了一种药物的作用机制。
基于多(二/三)核基序的临床相关系列铂类抗癌药物。工作
源于一个基本原则,即获得真正不同的抗肿瘤活性特征
对于临床使用的试剂,结构不同的 DNA 加合物的识别和加工的不同模式是
必需的。此类药物与靶 DNA 的相互作用不同于基于单核的药物
顺铂家族,事实上,与临床使用的任何 DNA 损伤剂不同。概念证明
这种方法的实用性是通过一种药物 BBR3464 进入人体 II 期试验而得到的。有了这个
随着技术的进步,基于顺铂的抗肿瘤药物的范式发生了改变。化学和生物学特性
这些药物认为它们应该被视为代表全新的 DNA 结构类别
修饰抗癌剂。了解这些新颖互动的本质以及它们如何发挥作用非常重要。
影响 DNA 功能,以充分发挥其临床潜力。
该提案将研究多核铂形成的 DNA 加合物的独特之处
我们实验室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 期试验显示出对通常不常见的癌症的明显反应模式
可用顺铂治疗,包括对黑色素瘤、胰腺癌和肺癌的反应。客观回应
II期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 突变肿瘤中具有活性,并且 BBR3464 治疗后 p53 的诱导程度最低。它是
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此类事件是否可能
被指示导致一种真正新的抗肿瘤活性模式。这是该项目的进一步长期目标
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导致设计出更好、更特异的药物来治疗癌症。
癌症的治疗。这些药物将与靶向药物联合使用,以提供更好的治疗效果
癌症患者的治疗方案。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导致设计出更好、更特异的药物来治疗癌症。
癌症的治疗。这些药物将与靶向药物联合使用,以提供更好的治疗效果
癌症患者的治疗方案。
项目成果
期刊论文数量(66)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Dinuclear platinum complexes containing planar aromatic ligands to enhance stacking interactions with proteins.
- DOI:10.1002/cmdc.201402052
- 发表时间:2014-06
- 期刊:
- 影响因子:3.4
- 作者:Ma, Erin S. F.;Daniel, A. Gerard;Farrell, Nicholas P.
- 通讯作者:Farrell, Nicholas P.
Nucleolar targeting by platinum: p53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction.
- DOI:10.1021/mp5006867
- 发表时间:2015-01-05
- 期刊:
- 影响因子:4.9
- 作者:Peterson EJ;Menon VR;Gatti L;Kipping R;Dewasinghe D;Perego P;Povirk LF;Farrell NP
- 通讯作者:Farrell NP
Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes.
- DOI:10.1016/j.jinorgbio.2012.10.007
- 发表时间:2013-02
- 期刊:
- 影响因子:3.9
- 作者:A. P. Neves;Michelle X.G. Pereira;E. Peterson;R. Kipping;Maria D. Vargas;F. Silva-Jr;J. Carneiro;Nicholas P. Farrell
- 通讯作者:A. P. Neves;Michelle X.G. Pereira;E. Peterson;R. Kipping;Maria D. Vargas;F. Silva-Jr;J. Carneiro;Nicholas P. Farrell
Platinum-based drugs and proteins: reactivity and relevance to DNA adduct formation.
- DOI:10.1016/j.jinorgbio.2013.01.007
- 发表时间:2013-05
- 期刊:
- 影响因子:3.9
- 作者:Pinato, Odra;Musetti, Caterina;Farrell, Nicholas P.;Sissi, Claudia
- 通讯作者:Sissi, Claudia
Circular dichroism study of the irreversibility of conformational changes induced by polyamine-linked dinuclear platinum compounds.
- DOI:10.1016/s0162-0134(02)00398-7
- 发表时间:2002-07
- 期刊:
- 影响因子:3.9
- 作者:T. D. McGregor;W. Bousfield;Y. Qu;N. Farrell
- 通讯作者:T. D. McGregor;W. Bousfield;Y. Qu;N. Farrell
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NICHOLAS P FARRELL其他文献
NICHOLAS P FARRELL的其他文献
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{{ truncateString('NICHOLAS P FARRELL', 18)}}的其他基金
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
新型铂类临床药物的机理研究
- 批准号:
2686173 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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:
6931019 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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:
6545213 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
新型铂类临床药物的机理研究
- 批准号:
6377194 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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:
6780926 - 财政年份:1998
- 资助金额:
$ 30.32万 - 项目类别:
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