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

描述（申请人提供）：顺铂是应用最广泛的化疗药物之一。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加合物阻断了参与DNA复制和DNA转录的酶。这些加合物引起细胞周期阻滞，最终导致细胞凋亡。然而，在癌症治疗和缓解后，经常会出现复发和对顺铂的耐药。肿瘤细胞耐药的主要机制是DNA修复增强。本建议的重点是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。这一机制是通过ICL的特定结构加工和ICL受损DNA的“实际”修复竞争介导的。为了证明我们的假设，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)利用体外技术和纯化蛋白进一步评估BER和MMR蛋白在顺铂ICL加工中的生化机制。了解顺铂疗效的途径和癌细胞发展克服药物的机制是至关重要的。这对于设计更好的治疗方案以及开发新的抗癌药物是必要的。没有这种认识，新的癌症治疗方法的发展就会受到限制。

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.