Biomodulation of anticancer drugs targeting DNA

靶向DNA的抗癌药物的生物调节

基本信息

批准号：
7619892
负责人：
France Carrier
金额：
$ 22.8万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619892
关键词：
Active Sites Acute leukemia Address Affect Affinity Aftercare Antibodies Antineoplastic Agents Apoptosis Architecture Binding Binding Proteins Binding Sites Biological Assay Cancer cell line Cell Cycle Cell Extracts Cell Line Cell physiology Cells Chromatin Cisplatin Classification Clinical Trials Design Code DNA DNA Binding Domain DNA Damage DNA Packaging DNA Sequence Data Diagnosis Digestion Doxorubicin Drug Delivery Systems Ellipticines Enzymes Exons France Gel Genes Goals HMGA1 gene Heterochromatin Histone Deacetylase Inhibitor Histone H1 Histone H1(s)Histone H3 Histone H4 Immunoprecipitation Institution Length MCF7 cell Malignant Neoplasms Measurement Measures Mediating Micrococcal Nuclease Modification Molecular Monitor Morphology Normal Cell Nuclear Nucleosomes Oncogenes Patients Pattern Pharmaceutical Preparations Phase Phase I Clinical Trials Phosphorylation Point Mutation Post-Translational Protein Processing Proteins Relapse Research Personnel Site Small Interfering RNA Southern Blotting Staphylococcal Protein A Structure Superhelical DNA Syndrome Testing Therapeutic Topoisomerase Transfection Trichostatin A U118 Vorinostat base c-myc Genes cancer cell cancer therapy carcinogenesis chromatin immunoprecipitation cytotoxic drug discovery ellipticine flexibility heterochromatin-specific nonhistone chromosomal protein HP-1 histone-binding proteins human H2AX protein improved killings mutant neoplastic cell overexpression prevent programs promoter succinyl-trialanine-4-nitroanilide transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hypothesis: We have recently shown that pre-treatment of several cancer cell lines with TSA or SANA, two Histone Deacetylase Inhibitors (HDACIs), increased the killing efficiency of VP-16, ellipticine, doxorubicin and cisplatin. Because no sensitizing effect was observed in normal cells or when the HDACIs were added after instead of before the anticancer drugs in cancer cells, we hypothesized that intrinsic differences between the chromatin of normal and cancer cells allow the HDACIs to increase the DNA accessibility of the anticancer drugs in the cancer cells. Specific Aims: To verify this hypothesis we will: 1) Determine if the chromatin compaction of normal and cancer cells is affected differently by the HDACIs. Bulk chromatin will be digested with Micrococcal Nuclease (MNase) and chromatin will also be digested at specific loci targeted by the anticancer drugs. In addition, chromatin from synchronized cells will be digested and the nucleosome repeat length will be measured. Levels of histone H1 phosphorylation and distribution of the heterochromatin protein HP1a and the histone H4 acetylated at Lys16 will also be evaluated as indicators of chromatin compaction. 2) Determine if the effect of HDACIs on drug accessibility is different on the chromatin of normal and cancer cells. This will be performed by a modified Chips assay to measure chromatin accessibility in the vicinity of the DNA sequences targeted by the anticancer drugs and by the PCR-stop assay. 3) Determine if histone binding proteins overexpressed in cancer cells contribute to the sensitizing effect of HDACIs. We will evaluate the potential enhancing effect of HMG-I/Y on HDACIs sensitization to anticancer drugs targeting the DNA or enzymes acting on the DNA. This will be performed by down regulating the levels of HMG-I/Y in cancer cells and by identifying the domain(s) sufficient to mediate this effect. Significance: Our initial study demonstrated that pre-treatment of cancer cells with HDACIs increased the killing efficiency of anticancer drugs. On November 2005, a Phase 1 clinical trial was approved at our institution to expand this study to patients with relapsed and/or acute leukemia and myeolodysplastic syndromes. This proposal will provide a better understanding of the basic mechanisms mediating this effect and will contribute to guide and develop mechanism-based therapeutics for cancer treatments.

描述（由申请人提供）：假设：我们最近表明，用 TSA 或 SANA（两种组蛋白脱乙酰酶抑制剂 (HDACIs)）预处理几种癌细胞系，可以提高 VP-16、玫瑰树碱、阿霉素和顺铂的杀伤效率。由于在正常细胞中没有观察到敏化作用，或者当 HDACIs 在癌细胞中添加抗癌药物之后而不是之前添加时，我们假设正常细胞和癌细胞染色质之间的内在差异使 HDACIs 能够增加抗癌药物的 DNA 可及性癌细胞中的药物。具体目标：为了验证这一假设，我们将：1) 确定正常细胞和癌细胞的染色质压缩是否受到 HDACIs 的不同影响。大量染色质将被微球菌核酸酶 (MNase) 消化，染色质也将在抗癌药物靶向的特定位点被消化。此外，同步化细胞的染色质将被消化，并测量核小体重复长度。组蛋白 H1 磷酸化水平以及异染色质蛋白 HP1a 和 Lys16 乙酰化组蛋白 H4 的分布也将作为染色质压缩的指标进行评估。 2) 确定 HDACIs 对药物可及性的影响在正常细胞和癌细胞的染色质上是否不同。这将通过改进的 Chips 测定来测量抗癌药物靶向的 DNA 序列附近的染色质可及性，并通过 PCR 终止测定来进行。 3) 确定癌细胞中过度表达的组蛋白结合蛋白是否有助于 HDACIs 的敏化作用。我们将评估 HMG-I/Y 对 HDACIs 对靶向 DNA 或作用于 DNA 的酶的抗癌药物的敏感性的潜在增强作用。这将通过下调癌细胞中的 HMG-I/Y 水平并通过鉴定足以介导这种作用的结构域来实现。意义：我们的初步研究表明，用 HDACIs 预处理癌细胞可提高抗癌药物的杀伤效率。 2005 年 11 月，我们机构批准了一项 1 期临床试验，将这项研究扩展到患有复发和/或急性白血病和骨髓增生异常综合征的患者。该提案将有助于更好地理解介导这种效应的基本机制，并将有助于指导和开发基于机制的癌症治疗方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Over Expression of Nucleophosmin and Nucleolin Contributes to the Suboptimal Activation of a G2/M Checkpoint in Ataxia Telangiectasia Fibroblasts.

核磷蛋白和核蛋白的过度表达导致共济失调毛细血管扩张成纤维细胞中 G2/M 检查点的次优激活。

DOI：
发表时间：
2010
期刊：
Molecular and cellular pharmacology
影响因子：
0
作者：
Nalabothula,Narasimharao;Chakravarty,Devulapalli;Pierce,Adam;Carrier,France
通讯作者：
Carrier,France

VorinostatSAHA Promotes Hyper-Radiosensitivity in Wild Type p53 Human Glioblastoma Cells.

VorinostatSAHA 促进野生型 p53 人胶质母细胞瘤细胞的超放射敏感性。

DOI：
发表时间：
2014
期刊：
Journal of clinical oncology and research
影响因子：
0
作者：
Diss,Eric;Nalabothula,NarasimhaRao;Nguyen,Duc;Chang,Elizabeth;Kwok,Young;Carrier,France
通讯作者：
Carrier,France

Enhanced translation by Nucleolin via G-rich elements in coding and non-coding regions of target mRNAs.

DOI：
10.1093/nar/gkr488
发表时间：
2011-10
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Abdelmohsen K;Tominaga K;Lee EK;Srikantan S;Kang MJ;Kim MM;Selimyan R;Martindale JL;Yang X;Carrier F;Zhan M;Becker KG;Gorospe M
通讯作者：
Gorospe M

Chromatin Modulation by Histone Deacetylase Inhibitors: Impact on Cellular Sensitivity to Ionizing Radiation.