Alkyltransferase Inhibitors for Cancer Chemotherapy
用于癌症化疗的烷基转移酶抑制剂
基本信息
- 批准号:7790704
- 负责人:
- 金额:$ 25.09万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1996
- 资助国家:美国
- 起止时间:1996-08-01 至 2012-04-30
- 项目状态:已结题
- 来源:
- 关键词:2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazoleAbbreviationsAcidsAlkylating AgentsAntineoplastic AgentsCarmustineCell Culture TechniquesCellsChemotherapy-Oncologic ProcedureClinical TrialsCrystallographyDNADeoxyguanosineDevelopmentDigestionDithiothreitolEstersExonucleaseExposure toFolateFolic AcidGoalsGuanineHumanIn VitroLengthMass Spectrum AnalysisMediatingMethylnitronitrosoguanidineModificationMolecular ModelsNitrosoguanidinesNormal CellNude MiceO(6)-Methylguanine-DNA MethyltransferaseO(6)-benzylguanineOligonucleotidesPharmaceutical PreparationsProdrugsProductionProgress ReportsPropertyPublishingRBBP9 geneResearch PersonnelResistanceResistance developmentSite-Directed MutagenesisSolubilitySourceTechniquesTestingTherapeuticTherapeutic IndexTumor Cell LineWorkXenograft procedurealkyltransferasebasedesignesterasefolate-binding proteinfollow-upimprovedinhibitor/antagonistinorganic phosphatekillingsmolecular modelingmutantneoplastic cellnovelpre-clinicalprogramsrepairedresearch studyresponsesuccesstemozolomidetumortumor specificitytumor xenograftuptake
项目摘要
DESCRIPTION (provided by applicant): Human O6-alkylguanine-DNA alkyltransferase (hAGT) is a major cause of resistance of tumor cells to killing by certain therapeutic methylating and chloroethylating agents. Inactivation of hAGT by O6-benzylguanine (BG) has been shown to sensitize human tumors to these alkylating agents in cell culture and to improve the therapeutic index against human tumor xenografts in nude mice. Clinical trials with BG indicate that this agent will be successful only in limited situations due to the lack of adequate potency and tumor specificity and the facile production of mutants of hAGT resistant to BG. Therefore, more potent and specific inhibitors are needed. The proposal has 3 specific aims to develop such compounds: (1) To understand the mechanism of the inactivation of hAGT by 2-amino- O4-benzylpteridine derivatives. We have shown that some of these compounds including O4-benzylfolic acid (BF) are potent inactivators of hAGT. In this aim, molecular modelling, crystallography, site-directed mutagenesis and powerful selection techniques to obtain informative mutants will be used to understand the basis for the improved activity of these compounds over BG, the reason that the inactivation is interfered with by the presence of DNA and to improve design of this class of compounds. (2) To investigate the relationship between folate transport and the ability of BF to inactivate cellular AGT and overcome AGT-mediated resistance to alkylating agents. These studies will follow up our preliminary studies that have shown that BF is much more effective at inactivating AGT in tumor cell lines that have high levels of folate transport. (3) Preliminary results also indicate that other folate derivatives of BG or O6-benzyl-2'-deoxyguanosine and oligodeoxynucleotides containing multiple BG residues also have properties that would provide improved AGT inhibitors. The ultimate goal of this aim is that by further study and appropriate modifications of these compounds, AGT inactivators can be made that fill the desired goals of increased solubility, increased potency against BG resistant mutants and tumor specificity. The development of resistance to anticancer agents is a major factor in limiting the success of these drugs. These experiments provide a means to reverse a well know source of resistance to alkylating agents that are used in such therapy. As such, they will increase the likelihood that these agents will produce therapeutic responses.
描述(由申请人提供):人类O6-烷基鸟嘌呤-DNA烷基转移酶(HAGT)是肿瘤细胞通过某些治疗性甲基化和氯乙基剂杀死肿瘤抗性的主要原因。 O6-苯二唑氨酸(BG)对HAGT的灭活已被证明可以使人类肿瘤在细胞培养中对这些烷基化剂敏感,并改善针对裸鼠中人类肿瘤异种移植的治疗指数。 BG的临床试验表明,由于缺乏足够的效力和肿瘤特异性以及抗BG耐药性突变体的便利产生,该药物只有在有限的情况下才能成功。因此,需要更有效和特定的抑制剂。该提案具有3个特定的目的旨在开发此类化合物:(1)了解2-氨基O4-苯二唑吡啶衍生物使HAGT失活的机理。我们已经表明,其中一些化合物在内,包括O4-苯二唑酸(BF)是HAGT的有效灭活剂。在此目的中,将使用分子建模,晶体学,定位诱变和强大的选择技术来获取信息性突变体,以了解这些化合物比BG的改善活性的基础,这是由于存在灭活而受到灭活的原因。 DNA并改善此类化合物的设计。 (2)研究叶酸转运与BF灭活细胞AGT并克服AGT介导的对烷基化剂的抗性之间的关系。这些研究将跟进我们的初步研究,这些研究表明,BF在具有高水平叶酸转运的肿瘤细胞系中失活的AGT更为有效。 (3)初步结果还表明,BG或O6-苯甲酰-2'-脱氧鸟苷的其他叶酸衍生物和包含多个BG残基的寡脱氧核苷酸也具有可改善AGT抑制剂的特性。这个目标的最终目标是,通过进一步研究并对这些化合物进行了适当的修改,可以使Agt灭活剂填补提高溶解度的期望目标,增加对BG抗性突变体和肿瘤特异性的效力。对抗癌剂的抵抗力的发展是限制这些药物成功的主要因素。这些实验提供了一种逆转在这种疗法中使用的烷基化剂的耐药性来源的方法。因此,它们将增加这些药物产生治疗反应的可能性。
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Multifaceted roles of alkyltransferase and related proteins in DNA repair, DNA damage, resistance to chemotherapy, and research tools.
- DOI:10.1021/tx200031q
- 发表时间:2011-05-16
- 期刊:
- 影响因子:4.1
- 作者:Pegg AE
- 通讯作者:Pegg AE
Substitution of aminomethyl at the meta-position enhances the inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine.
- DOI:10.1021/jm800675p
- 发表时间:2008-11-27
- 期刊:
- 影响因子:7.3
- 作者:Pauly GT;Loktionova NA;Fang Q;Vankayala SL;Guida WC;Pegg AE
- 通讯作者:Pegg AE
Effect of O6-alkylguanine-DNA alkyltransferase on genotoxicity of epihalohydrins.
- DOI:10.1002/em.20491
- 发表时间:2009-07
- 期刊:
- 影响因子:2.8
- 作者:Kalapila, Aley G.;Loktionova, Natalia A.;Pegg, Anthony E.
- 通讯作者:Pegg, Anthony E.
Plasma and CNS pharmacokinetics of O4-benzylfolic acid (O4BF) and metabolite in a non-human primate model.
非人类灵长类动物模型中 O4-苄基叶酸 (O4BF) 及其代谢物的血浆和 CNS 药代动力学。
- DOI:10.1007/s00280-010-1407-9
- 发表时间:2011
- 期刊:
- 影响因子:3
- 作者:Chuk,MeredithK;Cole,DianeE;McCully,Cynthia;Loktionova,NataliaA;Pegg,AnthonyE;Parker,RobertJ;Pauly,Gary;Widemann,BrigitteC;Balis,FrankM;Fox,Elizabeth
- 通讯作者:Fox,Elizabeth
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Sreenivas Kanugula其他文献
Sreenivas Kanugula的其他文献
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{{ truncateString('Sreenivas Kanugula', 18)}}的其他基金
Alkyltransferase Inhibitors for Cancer Chemotherapy
用于癌症化疗的烷基转移酶抑制剂
- 批准号:
7618467 - 财政年份:1996
- 资助金额:
$ 25.09万 - 项目类别:
Persistence of Alkylated DNA Carcinogenesis
烷基化 DNA 致癌作用的持续存在
- 批准号:
8018201 - 财政年份:1978
- 资助金额:
$ 25.09万 - 项目类别:
Persistence of Alkylated DNA Carcinogenesis
烷基化 DNA 致癌作用的持续存在
- 批准号:
7749554 - 财政年份:1978
- 资助金额:
$ 25.09万 - 项目类别:
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