Generation and characterization of adduct-specific anti cisplatin DNA antibodies

加合物特异性抗顺铂 DNA 抗体的生成和表征

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Cisplatin and carboplatin (platinum drugs) are among the most successful antitumor drugs and are used to treat testicular, breast, ovarian, bladder, neck and lung cancer. As with many antitumor agents, the efficacy of treatment can vary greatly from patient to patient and the occurrence of resistance is a significant problem. The therapeutic effect of the platinums is based on the formation of different types of DNA adducts, primarily intra- and interstrand crosslinks, by the reaction with two purine bases on one or two complementary strands of DNA. The resistance to platinum treatment occurs by a the up- or down-regulation of several processes, including metal transport in and out of the cell, intracellular metabolism and the removal of the cisplatin DNA adducts by DNA repair pathways. The primary hypothesis of the work proposed in this application is that by developing a monoclonal antibodies with specificity for the individual platinum DNA adducts in the genomes of cells we will be able to 1) determine which platinum adduct is the most therapeutically relevant one, 2) understand the repair mechanisms responsible for resistance, 3) test the sensitivity or resistance to platinum in tumor biopsies and 4) to select patients that are most likely to benefit from therapy and sparing those that are likely to be resistant the severe side effect associated with this type of treatment. In this R21 application, we propose to synthesize oligonucleotides containing the 1,2-GG-, 1,2-AG-, 1,3-GNG-intrastrand and 1,2-GC-interstrand platinum crosslinks, couple them to the KLH carrier protein and use them to immunize mice to generate monoclonal antibodies that recognize the individual adducts with high specificity. These monoclonal antibodies will be then further validated in cell lines with specific DNA repair defects. We predict that these reagents will enable us to show that platinum intrastrand crosslinks persist in cells with defects in the nucleotide excision repair (NER) pathway, while interstrand crosslinks will persist in cells with defects interstrand crosslink (ICL) repair pathwa. We will then measure platinum levels in breast and ovarian cancer cell lines of the NCI-60 collection, which have been characterized for drug sensitivity or resistance. We will determine whether the levels of a specific adduct or all adduct are elevated in platinum-responsive cell lines. Conversely, we will test whether a specific adduct is absent in resistant cell lines. We expect that upon completion of the studies proposed here we will have developed a set of unique reagents that will be of tremendous use for the research and medical community to determine which platinum adducts are clinically most relevant and to work toward developing a robust method to predict clinical outcomes of platinum treatments.
 描述(由申请人提供):顺铂和卡铂(铂类药物)是最成功的抗肿瘤药物之一,用于治疗睾丸癌、乳腺癌、卵巢癌、膀胱癌、颈癌和肺癌。与许多抗肿瘤药物一样,治疗效果因患者而异,并且耐药性的出现是一个重大问题。铂的治疗效果基于不同类型的 DNA 加合物的形成,主要是通过与一条或两条互补 DNA 链上的两个嘌呤碱基反应而形成的链内和链间交联。对铂治疗的耐药性是由几个过程的上调或下调引起的,包括金属进出细胞的转运、细胞内代谢以及通过 DNA 修复途径去除顺铂 DNA 加合物。本申请中提出的工作的主要假设是,通过开发对细胞基因组中各个铂 DNA 加合物具有特异性的单克隆抗体,我们将能够 1) 确定哪种铂加合物在治疗上最相关,2) 了解导致耐药性的修复机制,3) 测试肿瘤活检中对铂的敏感性或耐药性,以及 4) 选择最有可能受益的患者 避免那些可能对此类治疗产生耐药性的严重副作用。在此 R21 应用中,我们建议合成含有 1,2-GG-、1,2-AG-、1,3-GNG-链内和 1,2-GC-链间铂交联的寡核苷酸,将它们与 KLH 载体蛋白偶联,并用它们免疫小鼠以生成高特异性识别单个加合物的单克隆抗体。这些单克隆抗体将在具有特定 DNA 修复缺陷的细胞系中得到进一步验证。我们预测这些试剂将使我们能够证明铂链内交联在核苷酸切除修复(NER)途径缺陷的细胞中持续存在,而链间交联将在链间交联(ICL)修复途径缺陷的细胞中持续存在。然后,我们将测量 NCI-60 收集的乳腺癌和卵巢癌细胞系中的铂水平,这些细胞系已被表征为药物敏感性或耐药性。我们将确定铂敏感细胞系中特定加合物或所有加合物的水平是否升高。相反,我们将测试耐药细胞系中是否不存在特定的加合物。我们预计,在完成此处提出的研究后,我们将开发出一套独特的试剂,这些试剂将对研究和医学界发挥巨大作用,以确定哪些铂加合物在临床上最相关,并致力于开发一种稳健的方法来预测铂治疗的临床结果。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Orlando D. Scharer其他文献

Orlando D. Scharer的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Orlando D. Scharer', 18)}}的其他基金

Synthesis, Structure and Repair of DNA Interstrand Crosslinks
DNA 链间交联的合成、结构和修复
  • 批准号:
    8402673
  • 财政年份:
    2012
  • 资助金额:
    $ 20.41万
  • 项目类别:
Synthesis, Structure and Repair of DNA Interstrand Crosslinks
DNA 链间交联的合成、结构和修复
  • 批准号:
    8657932
  • 财政年份:
    2012
  • 资助金额:
    $ 20.41万
  • 项目类别:
Synthesis, Structure and Repair of DNA Interstrand Crosslinks
DNA 链间交联的合成、结构和修复
  • 批准号:
    8495292
  • 财政年份:
    2012
  • 资助金额:
    $ 20.41万
  • 项目类别:
Coordination of the late steps of human nucleotide excision repair
人类核苷酸切除修复后期步骤的协调
  • 批准号:
    7899485
  • 财政年份:
    2009
  • 资助金额:
    $ 20.41万
  • 项目类别:
Coordination of the late steps of human nucleotide excision repair
人类核苷酸切除修复后期步骤的协调
  • 批准号:
    7500156
  • 财政年份:
    2007
  • 资助金额:
    $ 20.41万
  • 项目类别:
Coordination of the late steps of human nucleotide excision repair
人类核苷酸切除修复后期步骤的协调
  • 批准号:
    7674676
  • 财政年份:
    2007
  • 资助金额:
    $ 20.41万
  • 项目类别:
Coordination of the late steps of human nucleotide excision repair
人类核苷酸切除修复后期步骤的协调
  • 批准号:
    7371386
  • 财政年份:
    2007
  • 资助金额:
    $ 20.41万
  • 项目类别:
Coordination of the late steps of human nucleotide excision repair
人类核苷酸切除修复后期步骤的协调
  • 批准号:
    7912876
  • 财政年份:
    2007
  • 资助金额:
    $ 20.41万
  • 项目类别:

相似海外基金

Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
  • 批准号:
    10591918
  • 财政年份:
    2023
  • 资助金额:
    $ 20.41万
  • 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
  • 批准号:
    23K15383
  • 财政年份:
    2023
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
  • 批准号:
    23H03556
  • 财政年份:
    2023
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
  • 批准号:
    23K17212
  • 财政年份:
    2023
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
  • 批准号:
    22H03519
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
  • 批准号:
    563657-2021
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10521849
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
  • 批准号:
    10671022
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
  • 批准号:
    10670918
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
Adverse Effects of Using Laser Diagnostics in High-Speed Compressible Flows
在高速可压缩流中使用激光诊断的不利影响
  • 批准号:
    RGPIN-2018-04753
  • 财政年份:
    2022
  • 资助金额:
    $ 20.41万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了