Novel Role of Base Excision Repair and Mismatch Repair in Cisplatin Sensitivity

碱基切除修复和错配修复在顺铂敏感性中的新作用

• 批准号: 8620667
• 负责人: Steve M Patrick
• 金额: $ 30.06万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620667
• 关键词: Address; Affect; Aftercare; Antineoplastic Agents; Apoptosis; Base Excision Repairs; Binding; Biochemical; Biological Assay; Cell Cycle Arrest; Cell Line; Cells; Cisplatin; Clinic; Clinical; Complement; Cytosine; DNA; DNA Adducts; DNA Damage; DNA Interstrand Cross-Link Repair; DNA Repair; DNA Repair Pathway; DNA Structure; DNA biosynthesis; Data; Deamination; Dependence; Development; Disease remission; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Genetic Transcription; Goals; Head and Neck Cancer; Head and neck structure; Health; Human; In Vitro; Knockout Mice; Lead; Lyase; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mismatch Repair; Mitomycins; Modeling; Monitor; Mutation; Nature; Nucleotide Excision Repair; Null Lymphocytes; Ovarian; Pathway interactions; Pharmaceutical Preparations; Phenotype; Platinum; Play; Process; Protein Binding; Proteins; Resistance; Role; Site; Structure; Techniques; Testing; Treatment Protocols; Uracil; Work; adduct; base; cancer cell; cancer recurrence; cancer therapy; crosslink; cytotoxic; cytotoxicity; design; inhibitor/antagonist; killings; methoxyamine; mutant; neoplastic cell; novel; oxaliplatin; protein complex; repaired; resistance mechanism; synthetic construct; transplatin; uracil-DNA glycosylase

DESCRIPTION (provided by applicant): Cisplatin is one of the most widely used chemotherapeutic drugs. It is primarily used in the treatment of testicular, ovarian, head and neck and lung cancers. The cytotoxic effects of cisplatin have been attributed to DNA adducts which block the enzymes involved in DNA replication and DNA transcription. These adducts cause cell cycle arrest which eventually leads to apoptosis. Frequently, however, after treatment and remission of the cancer, recurrence and resistance to cisplatin occurs. A major mechanism of this resistance in tumor cells is enhanced DNA repair. This proposal focuses on the pathways that play a role in cisplatin effectiveness. We hypothesize that base excision repair (BER) and mismatch repair (MMR) play vital roles in maintaining cisplatin sensitivity through a unique mechanism that is dependent on interstrand cross-links (ICLs). This mechanism is mediated through specific structural processing of the ICLs and competition with 'actual' repair of the ICL damaged DNA. To address our hypothesis, we will conduct the following specific aims 1) elucidate the role of BER proteins in cisplatin sensitivity and ICL repair; 2) determine the role of MMR proteins in cisplatin sensitivity, ICL repair and mutation avoidance; and 3) use in vitro techniques and purified proteins to further assess the biochemical mechanisms of BER and MMR proteins in cisplatin ICL processing. It is critical to understand the pathways involved in cisplatin efficacy and mechanisms that cancer cells develop to overcome the drug. This is imperative for the design of better treatment protocols as well as in the development of new anticancer agents. Without this understanding, the development of new cancer treatment is limited.

描述（由申请人提供）：顺铂是最广泛使用的化疗药物之一。它主要用于治疗睾丸癌、卵巢癌、头颈癌和肺癌。顺铂的细胞毒性作用归因于DNA加合物，其阻断参与DNA复制和DNA转录的酶。这些加合物导致细胞周期停滞，最终导致细胞凋亡。然而，在癌症治疗和缓解后，经常发生复发和对顺铂的耐药性。肿瘤细胞中这种抗性的主要机制是增强的DNA修复。该提案侧重于在顺铂有效性中发挥作用的途径。我们假设碱基切除修复（BER）和错配修复（MMR）通过依赖于链间交联（ICLs）的独特机制在维持顺铂敏感性方面发挥重要作用。这种机制是通过ICL的特定结构加工和与ICL受损DNA的“实际”修复竞争来介导的。为了解决我们的假设，我们将进行以下具体目标：1）阐明BER蛋白在顺铂敏感性和ICL修复中的作用; 2）确定MMR蛋白在顺铂敏感性、ICL修复和突变避免中的作用; 3）使用体外技术和纯化的蛋白质进一步评估BER和MMR蛋白在顺铂ICL加工中的生化机制。了解顺铂疗效所涉及的途径以及癌细胞克服药物的机制至关重要。这对于设计更好的治疗方案以及开发新的抗癌药物至关重要。没有这种理解，新的癌症治疗方法的发展是有限的。

项目成果

Gap Junction Intercellular Communication Positively Regulates Cisplatin Toxicity by Inducing DNA Damage through Bystander Signaling.

• DOI: 10.3390/cancers10100368
• 发表时间: 2018-10-02
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Arora S;Heyza JR;Chalfin EC;Ruch RJ;Patrick SM
• 通讯作者: Patrick SM

Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells.

• DOI: 10.1016/j.dnarep.2010.03.010
• 发表时间: 2010-07-01
• 期刊: DNA repair
• 影响因子: 3.8
• 作者: Arora S;Kothandapani A;Tillison K;Kalman-Maltese V;Patrick SM
• 通讯作者: Patrick SM

Identification of small molecule inhibitors of ERCC1-XPF that inhibit DNA repair and potentiate cisplatin efficacy in cancer cells.

• DOI: 10.18632/oncotarget.12072
• 发表时间: 2016-11-15
• 期刊: Oncotarget
• 作者: Arora S;Heyza J;Zhang H;Kalman-Maltese V;Tillison K;Floyd AM;Chalfin EM;Bepler G;Patrick SM
• 通讯作者: Patrick SM