Mechanistic Studies on New Platinum Clinical Agents
Mechanistic Studies on New Platinum Clinical Agents
批准号:
7476038
负责人:
NICHOLAS P FARRELL
金额:
$28.14万
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-09-30 至 2008-04-30
关键词:
AffectAffinityAffinity LabelsAntineoplastic AgentsBBR 3464BindingBiologicalCancer PatientCell DeathChargeChemical StructureChemicalsCisplatinClassClinicalCombination ChemotherapyComplexCoupledCytosolDNADNA AdductsDNA BindingDNA Interstrand CrosslinkingDNA RepairDrug Delivery SystemsDrug KineticsEventFamilyFractionationFrequenciesGliomaGoalsHumanLaboratoriesLeadLinkMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of ovaryMeasuresMembrane PotentialsMinor GrooveMitochondriaModelingMolecularMolecular ConformationMolecular StructureMononuclearNatureNon-Small-Cell Lung CarcinomaNuclearNucleotide Excision RepairPancreasPathway interactionsPatternPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhospholipidsPlatinumPlatinum CompoundsPolyaminesPolymersProcessPropertyProteinsRNARangeRelapseSeriesSignal PathwaySignal TransductionSpecificityStructureTP53 geneTechniquesTissuesTreatment ProtocolsVertebral columnWorkadductaffinity labelinganalogantitumor agentbasecancer therapyclinically relevantconceptcrosslinkcytotoxiccytotoxicitydesigninorganic phosphateintercalationmelanomamutantnovelpreclinical studyprotein activationrepairedresponsestemtumoruptake
中文摘要
这项更新建议的直接意义是研究一种临床的作用机制
英文摘要
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.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
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
Metals in Medicine Gordon Research Conference
-
批准号:6535514
-
项目类别:
-
资助金额:$0.5万
-
财政年份:2002
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Metals in Medicine Gordon Research Conference
-
批准号:6777591
-
项目类别:
-
资助金额:$0.53万
-
财政年份:2002
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Metals in Medicine Gordon Research Conference
-
批准号:6615767
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2002
-
负责人:NICHOLAS P FARRELL
-
依托单位:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
-
批准号:2686173
-
项目类别:
-
资助金额:$29.12万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:8235958
-
项目类别:
-
资助金额:$30.32万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:6931019
-
项目类别:
-
资助金额:$30.55万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:6545213
-
项目类别:
-
资助金额:$31.73万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
-
批准号:6377194
-
项目类别:
-
资助金额:$27.35万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:8035451
-
项目类别:
-
资助金额:$30.32万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:6780926
-
项目类别:
-
资助金额:$30.55万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
-
批准号:6173960
-
项目类别:
-
资助金额:$26.55万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
MECHANISTIC STUDIES ON NEW PLATINUM CLINICAL AGENTS
-
批准号:2896636
-
项目类别:
-
资助金额:$26.1万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:7097323
-
项目类别:
-
资助金额:$29.83万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:7466829
-
项目类别:
-
资助金额:$31.15万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:7766244
-
项目类别:
-
资助金额:$29.98万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:6619888
-
项目类别:
-
资助金额:$30.63万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
Mechanistic Studies on New Platinum Clinical Agents
-
批准号:7618730
-
项目类别:
-
资助金额:$31.22万
-
财政年份:1998
-
负责人:NICHOLAS P FARRELL
-
依托单位:
海外基金