Novel Targets in Cancer Chemotherapy: Chemical Biology of Guanine Alkylation

癌症化疗的新靶点：鸟嘌呤烷基化的化学生物学

基本信息

批准号：
9788282
负责人：
Michael P Stone
金额：
$ 138.95万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788282
关键词：
Adjuvant Adjuvant Chemotherapy Adjuvant Therapy Adriamycin PFS Adverse effects Aldehydes Alkylating Agents Alkylation Amines Amino Sugars Anthracycline Antibiotics Anthracyclines Antibiotics Antineoplastic Agents Base Excision Repairs Base Pairing Biochemical Biological Biological Markers Biology Breast Cancer Patient Bypass CRISPR/Cas technology Cells Charge Chemicals Chemistry Chemotherapy-Oncologic Procedure Clinical Complex Cyclophosphamide DNA DNA Alkylation DNA Damage DNA Sequence DNA Structure DNA biosynthesis Deoxyribose Depurination Detection Doxorubicin Drug Interactions Electrospray Ionization Equilibrium Genetic Transcription Genomic Instability Guanine Human Hydrazones Hydroxylamine Imidazole Individual Isomerism Isotopes Knowledge Lesion Malignant Neoplasms Mammalian Cell Measures Mechlorethamine Methods Minor Groove Mitoxantrone Modality Molecular Conformation Mustard Agent Nitrogen Normal Cell Organ Outcome Oximes Patient Monitoring Patients Pharmaceutical Preparations Phase Polymerase Positioning Attribute Process Production Reagent Refractory Regimen Rest Site Site-Directed Mutagenesis Solid Structure System Therapeutic Thiotepa Tissues Treatment Efficacy Treatment Protocols adduct analog analytical method anomer antibiotic design antitumor agent base cancer cell cancer therapy chemical function chemotherapeutic agent chemotherapy chromophore crosslink cytotoxic cytotoxicity design effective therapy formamide genotoxicity improved innovation insight malignant breast neoplasm novel novel strategies programs real time monitoring repaired response sugar therapy design tumor vector

项目摘要

DNA alkylating agents, including nitrogen mustards (NM) such as cyclophosphamide (CPA), remain in heavy use as anti-cancer agents. They are employed in adjuvant chemotherapy regimens, such as the AC (anthracycline-CPA) therapy frequently administered to breast cancer patients. The primary site of alkylation in DNA is the N7-guanine position. This Program focuses upon chemistry and biology that happens after N7-dG alkylation: the NM N7-alkylated guanines undergo interstrand cross-link formation (ICL), base-induced ring-opening, yielding stable alkyl-formamidopyrimidine (N5-substituted-Fapy) lesions, and depurination, yielding apurinic (AP) sites. These types of complex DNA damage are may contribute substantially to the mechanisms of action of NM agents, including cytoxicity. Knowledge of the spectrum of complex DNA damage created by NM agents during therapy and the biological processing of this damage is critical for the design of effective treatment regimens. We have shown that the anthracyline antibiotic doxorubicin (Adriamycin), a component of AC therapy, forms covalent conjugates with AP sites, a previously unrecognized activity for this drug. Thus, AP sites formed as a consequence of NM treatment or as base excision repair (BER) intermediates provide targets for adjuvant therapies designed to increase cytotoxicity. Complex DNA damage arising from rearrangement of N7-dG alkylation sites has until now been understudied, in part, due to an inability to rigorously prepare DNAs containing such damage for biological, biochemical, and structural studies. Insights gained from our Program will yield fundamental and applied understanding of complex DNA damage arising from DNA alkylation and its detection in cellular DNA, innovative syntheses for the production and characterization of DNAs containing site-specific complex damage, structural understanding of how complex damage and AP site conjugation products alters DNA structure, and modulates repair and replication, effective design of anthracycline analogs targeted to AP sites, new biomarkers and analytical methods with which to monitor real time therapeutic efficacy in patients undergoing chemotherapy, and improved adjuvant therapy regimens designed to maximize cytotoxic response in cancer vs normal cells.

DNA烷基化剂，包括氮芥末（NM），例如环磷酰胺（CPA），保留在大量用作抗癌代理商。它们被用于辅助化疗方案，例如经常针对乳腺癌患者进行的AC（ACLACYCLINE-CPA）疗法。主要地点 DNA中的烷基化是N7-瓜氨酸的位置。该计划的重点是化学和生物学发生在N7-DG烷基化之后：NM NM N7烷基化的鸟嘌呤经历链间交联的形成（ICL），碱诱导的环，产生稳定的烷基氨基酰胺酰胺（N5-取代型疗法）病变和脱泌量产生源自膜的（AP）位点。这些类型的复杂DNA损伤可能在包括细胞毒性在内的NM剂的作用机理上有效。了解 NM药物在治疗期间和生物加工过程中造成的复杂DNA损伤的光谱这种损害对于设计有效治疗方案至关重要。我们已经证明了 AC疗法的一种成分，蒽固苯基抗生素阿霉素（Adrimycin）形成共价结合物使用AP位点，该药物的先前未被认可的活性。因此，AP站点形成 NM治疗或作为基础切除修复（BER）中间体为辅助治疗提供目标旨在增加细胞毒性。 N7-DG烷基化重排引起的复杂DNA损伤到目前为止，该站点必须部分研究，部分原因是无法严格准备含有DNA的DNA 生物学，生化和结构研究的这种损害。从我们的计划中获得的见解将对DNA烷基化引起的复杂DNA损伤产生基本和应用理解它在细胞DNA中的检测，用于生产和表征DNA的创新合成包含特定地点的复杂破坏，对复杂损害和AP站点的结构性理解共轭产品改变了DNA结构，并调节维修和复制，有效设计针对AP网站，新生物标志物和分析方法的蒽环类似物可以监测对接受化疗的患者的实时治疗功效，并改善了辅助治疗旨在最大化癌症与正常细胞中细胞毒性反应的方案。