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DNA DAMAGE AND GENE EXPRESSION IN BREAST CANCER

DNA DAMAGE AND GENE EXPRESSION IN BREAST CANCER
乳腺癌中的 DNA 损伤和基因表达
批准号:
2096925
负责人:
David A. Gewirtz
金额:
$9.31万
依托单位国家:
美国
项目类别:
财政年份:
1995
资助国家:
美国
项目状态:
已结题
起止时间:
1995-08-16 至 1998-07-31

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中文摘要
翻译
介导细胞生长抑制的生化和分子扰动 而破坏DNA的抗肿瘤药物的细胞毒性作用并不 明白本申请中提出的研究基于 c-myc表达下调的假设 癌基因和myc癌蛋白水平和活性的改变 可能是一种生长停滞途径的关键成分, DNA损伤&在MCF-7乳腺肿瘤细胞中。为了验证这一假设, 我们提出用c-myc基因转染MCF-7细胞, 由组成型启动子驱动的构建体减少或消除 对拓扑异构酶II抑制剂VM-26和m-AMSA的敏感性; 相反,K562人白血病细胞的类似转染(其中c-myc 似乎不参与生长调节), 表达的c-myc应该不会改变细胞对这些药物的敏感性。的 c-myc下调的性质将通过区分 VM-26和m-AMSA在转录水平(转录本 起始和延伸)和转录稳定性; 在对VM-26和m-AMSA的细胞应答中的c-myc启动子区 将通过使用myc监测药物对CAT活性的影响来建立 启动子-CAT构建体转染到MCF-7细胞中。联盟 “具有生长停滞的myc癌蛋白”将通过测定 VM-26和m-AMSA对癌蛋白水平的影响, 癌蛋白的状态,以及癌蛋白与其共有区的结合 顺序测定各种DNA损伤药物的能力(和 电离辐射)以产生c-myc表达的间接调节 和生长停滞将有助于确定c-myc是否均匀 参与MCF-7细胞对DNA损伤的细胞反应。最后, c-myc表达下调与生长停滞相关的范例 对DNA损伤的反应将在其他实验模型中进行评估 乳腺癌
英文摘要
The biochemical and molecular perturbations which mediate the cytostatic and cytotoxic effects of antineoplastic drugs which damage DNA are not understood. The studies proposed in this application are predicated upon the hypothesis that down regulation of the expression of the c-myc oncogene and alterations in the levels and activity of the myc oncoprotein may be critical components of one pathway of growth arrest in response to DNA damage& in MCF-7 breast tumor cells. In order to test this hypothesis, we propose to demonstrate that transfection of MCF-7 cells with a c-myc construct driven by a constitutive promoter reduces or abrogate sensitivity to the topoisomerase II inhibitors, VM-26 and m-AMSA; in contrast, a similar transfection of K562 human leukemic cells (where c-myc appears to be uninvolved in growth regulation) with constitutively expressed c-myc should fail to alter cell sensitivity to these drugs. The nature of c-myc down-regulation will be defined by discriminating between effects of VM-26 and m-AMSA at the level of transcription (transcript initiation and elongation) and transcript stability; the involvement of the c-myc promoter region in the cellular response to VM-26 and m-AMSA will be established by monitoring drug effects on CAT activity using a myc promoter-CAT construct transfected into MCF-7 cells. The association of the myc oncoprotein with growth arrest 'will be defined by determining the influence of VM-26 and m-AMSA on oncoprotein levels, the phosphorylation state of the oncoprotein, and binding of the oncoprotein to its consensus sequence. Determination of the capacity of various DNA damaging drugs (and ionizing radiation) to produce collateral modulation of c-myc expression and growth arrest will serve to establish whether c-myc is uniformly involved in the cellular response to DNA damage in MCF-7 cells. Finally, the paradigm relating down-regulation of c-myc expression to growth arrest in response to DNA damage will be evaluated in other experimental models of breast cancer.
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A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells
  • 批准号:
    10360542
  • 项目类别:
  • 资助金额:
    $49.92万
  • 财政年份:
    2021
  • 负责人:
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  • 依托单位:
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  • 批准号:
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  • 项目类别:
  • 资助金额:
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  • 财政年份:
    2021
  • 负责人:
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  • 依托单位:
A sequential therapeutic strategy of senescence induction and senolytics for elimination of surviving residual breast tumor cells
  • 批准号:
    10746519
  • 项目类别:
  • 资助金额:
    $4.39万
  • 财政年份:
    2021
  • 负责人:
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Use of senolytics to enhance chemotherapeutic efficacy in lung cancer
  • 批准号:
    9765748
  • 项目类别:
  • 资助金额:
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  • 财政年份:
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  • 负责人:
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  • 依托单位:
海外基金