Iron, NO, and Lipid Peroxides in Photodynamic Therapy
Iron, NO, and Lipid Peroxides in Photodynamic Therapy
批准号:
7363708
负责人:
Albert Girotti
金额:
$24.8万
依托单位国家:
美国
项目类别:
财政年份:
1996
资助国家:
美国
项目状态:
已结题
起止时间:
1996-12-15 至 2011-02-28
关键词:
AcheAffectApoptosisApoptoticBindingBiochemicalBiological ModelsCell DeathCell membraneCellsCessation of lifeCharacteristicsChemicalsConditionCyclic GMPDataDetectionDevelopmentDoseElectrophoretic Mobility Shift AssayEmployee StrikesEncapsulatedEnd PointEndothelial CellsEndotheliumEnergy MetabolismEnvironmental Risk FactorEnzymesErythrocyte GhostEventFerritinFluorescence MicroscopyFosteringFree RadicalsGenerationsGrantHemeHumanImmunoblottingIn VitroInflammationIon PumpsIronIron-Regulatory ProteinsKineticsLactate DehydrogenaseLearningLesionLightLipid PeroxidationLipid PeroxidesLipidsLiposomesLocalizedMC 540MCF7 cellMammary NeoplasmsMediatingMembraneMembrane LipidsMetabolicMitochondriaModalityModelingMolecularNa(+)-K(+)-Exchanging ATPaseNecrosisNitric OxideNitric Oxide DonorsOxygenasesPharmaceutical PreparationsPhotochemotherapyPhotosensitizing AgentsPlayPredispositionProcessProductionProteinsPumpReactionRelative (related person)Research PersonnelResidual stateResistanceRoleSignal TransductionSinglet OxygenSolid NeoplasmStressSystemTechniquesTestingTherapeuticThin Layer ChromatographyTimeTreatment EfficacyUnited States Food and Drug AdministrationVascular Systemascorbatebasecancer therapycell killingdesireinsightirradiationkillingsmacrophagemembrane modelneoplastic cellnovelnovel strategiesperoxidationpreconditioningprogramsprotoporphyrin IXreceptorresearch studytumor
中文摘要
光动力疗法(PDT)是一种多组分癌症治疗方法,其中肿瘤暴露于致命的单线辐射中
英文摘要
Photodynamic therapy (PDT) is a multicomponent cancer treatment in which tumors are exposed to lethal singlet
oxygen ('O2)-mediated photooxidative stress induced by a localized sensitizing drug. Much has been learned about
mechanism of tumor cell photokilling by various sensitizers, apoptosis (programmed cell death) occurring in some
cases and necrosis (non-programmed death) in others. However, the role of metabolic and environmental factors in
PDT-induced apoptotic vs. necrotic cell death are still not well understood. Studies supported by the existing grant have
focused on the effects of nitric oxide (NO) in this regard. Using breast tumor cells metabolically sensitized with
protoporphyrin IX (PpIX), we found that (i) NO delivered during irradiation (NO-now) protected against necrotic
photokilling by inhibiting free radical (chain) peroxidation of plasma membrane (PM) lipids; importantly, residual
killing was switched from necrosis to apoptosis; (ii)NO delivered much earlier and no longer present during irradiation
(NO-then) inhibited photokilling as well, preliminary data suggesting involvement of an iron signalingmechanism. In a
liposome system, NO also protected PpIX from photodegradation, thus prolonging its 'Degenerating lifetime. The
proposed studies will delve more deeply into these novel effects of NO with the following hypotheses proposed: (a)
NO-now and NO-then generated by neighboring microvascularcells can enhance tumor cell resistance to PDT killing;
(b) By inhibiting PM lipid chain peroxidation, NO-now can foster apoptosis by reducing ion pump inactivation and
membrane permeabilization, thereby supporting pro-apoptotic energy metabolism; (c) By also protecting membrane-
bound sensitizer from free radical-mediated degradation, NO-now can result in a "selection" for pro-apoptotic !O2
targets. The proposed in vitro studies for testing these hypotheses will involve model membranes, two human breast
tumor lines (COH-BR1, MCF-7), PpEX and merocyanine 540 (MC540) as sensitizers, chemical and cellular
(macrophage, endothelial) NO donors, and techniques such as fluorescence microscopy, spectrofluorimetry,
immunoblotting, electrophoretic mobility shift assays, and high-performanceliquid and thin layer chromatography with
electrochemical and phosphorimaging detection, respectively. The specific plan is to investigate (i) sensitizer
protection by NO-now with prolonged !O2 photogeneration in model systems and cells; (ii)ability of NO-now to
facilitate apoptotic photokilling while inhibiting necrosis; (iii) mechanisms by which NO-now accommodatesapoptosis;
(iv) characteristics of NO-then-induced photoresistance; and (v) underlying mechanisms of NO-then-induced resistance.
Although significant NO is produced by macrophages and endothelial cells in tumor vascular systems, little isknown
about how it might impact PDT efficacy. These studies will provide important new insights along these lines, and in
the case of NO-now may suggest novel approaches for accommodating apoptosis in PDT,this end-point beingpreferred
over necrosis because inflammation is minimized.
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会议论文
ROLE OF OXIDIZED CARDIOLIPIN TRANSLOCATION IN OXIDATIVE STRESS-INDUCED APOPTOSIS
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批准号:7817192
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项目类别:
-
资助金额:$31.51万
-
财政年份:2007
-
负责人:Albert Girotti
-
依托单位:
ROLE OF OXIDIZED CARDIOLIPIN TRANSLOCATION IN OXIDATIVE STRESS-INDUCED APOPTOSIS
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批准号:7414349
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项目类别:
-
资助金额:$31.51万
-
财政年份:2007
-
负责人:Albert Girotti
-
依托单位:
ROLE OF OXIDIZED CARDIOLIPIN TRANSLOCATION IN OXIDATIVE STRESS-INDUCED APOPTOSIS
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批准号:7617519
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项目类别:
-
资助金额:$31.51万
-
财政年份:2007
-
负责人:Albert Girotti
-
依托单位:
ROLE OF OXIDIZED CARDIOLIPIN TRANSLOCATION IN OXIDATIVE STRESS-INDUCED APOPTOSIS
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批准号:7264183
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项目类别:
-
资助金额:$32.8万
-
财政年份:2007
-
负责人:Albert Girotti
-
依托单位:
INTERMEMBRANE TRANSFER OF CHOLESTEROL HYDROPEROXIDES
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批准号:6639963
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项目类别:
-
资助金额:$3.96万
-
财政年份:2001
-
负责人:Albert Girotti
-
依托单位:
INTERMEMBRANE TRANSFER OF CHOLESTEROL HYDROPEROXIDES
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批准号:6335650
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项目类别:
-
资助金额:$3.84万
-
财政年份:2001
-
负责人:Albert Girotti
-
依托单位:
INTERMEMBRANE TRANSFER OF CHOLESTEROL HYDROPEROXIDES
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批准号:6540810
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项目类别:
-
资助金额:$3.85万
-
财政年份:2001
-
负责人:Albert Girotti
-
依托单位:
LIPID HYDROPEROXIDE CYTOTOXICITY AND DETOXIFICATION
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批准号:6350202
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项目类别:
-
资助金额:$17.07万
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财政年份:1998
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负责人:Albert Girotti
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依托单位:
LIPID HYDROPEROXIDE CYTOTOXICITY AND DETOXIFICATION
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批准号:2616909
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项目类别:
-
资助金额:$17.57万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
Lipid Hydroperoxide Cytotoxicity and Detoxification
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批准号:7238521
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项目类别:
-
资助金额:$28.48万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
Lipid Hydroperoxide Cytotoxicity and Detoxification
-
批准号:6689148
-
项目类别:
-
资助金额:$30.04万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
LIPID HYDROPEROXIDE CYTOTOXICITY AND DETOXIFICATION
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批准号:6150235
-
项目类别:
-
资助金额:$16.57万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
Lipid Hydroperoxide Cytotoxicity and Detoxification
-
批准号:6787300
-
项目类别:
-
资助金额:$30.04万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
Lipid Hydroperoxide Cytotoxicity and Detoxification
-
批准号:7095273
-
项目类别:
-
资助金额:$29.33万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
LIPID HYDROPEROXIDE CYTOTOXICITY AND DETOXIFICATION
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批准号:2871909
-
项目类别:
-
资助金额:$16.51万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
Lipid Hydroperoxide Cytotoxicity and Detoxification
-
批准号:6931067
-
项目类别:
-
资助金额:$30.04万
-
财政年份:1998
-
负责人:Albert Girotti
-
依托单位:
IRON, NO, AND LIPID PEROXIDES IN PHOTODYNAMIC THERAPY
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批准号:2608146
-
项目类别:
-
资助金额:$18.55万
-
财政年份:1996
-
负责人:Albert Girotti
-
依托单位:
IRON, NO, AND LIPID PEROXIDES IN PHOTODYNAMIC THERAPY
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批准号:2009781
-
项目类别:
-
资助金额:$21.43万
-
财政年份:1996
-
负责人:Albert Girotti
-
依托单位:
Iron, NO, and Lipid Peroxide in Photodynamic Therapy
-
批准号:8677707
-
项目类别:
-
资助金额:$24.15万
-
财政年份:1996
-
负责人:Albert Girotti
-
依托单位:
IRON, NO, AND LIPID PEROXIDES IN PHOTODYNAMIC THERAPY
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批准号:6513417
-
项目类别:
-
资助金额:$24.98万
-
财政年份:1996
-
负责人:Albert Girotti
-
依托单位:
海外基金