DNA损伤及修复

1、DNA repair pathways as targets for cancer therapyu DNA-damage agents in cancer treatmentu Efficient repair of chemotherapy lesionsu DNA repair inhibitors in combination therapyContentsDNA-damage agents 1. Radiotherapy and radiomimetics u Ionizing radiation can cause single-strand breaks (SSBs) and d

2、ouble-strand breaks (DSBs) in the DNA double helix backbone. u Radiomimetic agents Bleomycin(博来霉素) cause replication-independent DSBs that can kill non-replicating cells,such treatments can also rapidly prevent DNA replication by activation of cell-cycle checkpoints to avoid formation of toxic DNA r

3、eplication lesions.DNA-damage agents 2. Alkylating agents u Monofunctional alkylating agents（单功能烷化剂）（单功能烷化剂） Have one active moiety that modifies single bases. Alkylsulphonates(烷基磺酸盐), Nitrosourea compounds(亚硝基脲化合物), Temozolomide(替莫唑胺)u Bifunctional alkylating agents （双功能烷化剂）（双功能烷化剂） Have two reacti

4、ve sites and crosslink DNA with proteins or, alternatively, crosslink two DNA bases within the same DNA strand or on opposite DNA strands. Nitrogen mustard(氮芥),Mitomycin C (丝裂霉素C),Cisplatin(顺铂)等 DNA-damage agents3. Antimetabolites u Methotrexate(甲氨蝶呤),5-fluorouracil (5-FU) and 6-Mercaptopurine (6-巯基

5、嘌呤), resemble nucleotides, nucleotide precursors or cofactors required for nucleotide biosynthesis and act by inhibiting nucleotide metabolism pathways, thus depleting cells of dNTPs.u They can also impair replication fork(复制叉) progression by becoming incorporated into the DNA.DNA-damage agents4. To

6、poisomerase inhibitors u Topoisomerases are a group of enzymes that resolve torsional strains imposed on the double helix during DNA replication, they induce transient DNA breaks to relax supercoiled DNA or allow DNA strands to pass through each other.u Inhibitors：Camptothecins(喜树碱), Etoposide (VP16

7、,依托泊苷)5. Replication inhibitors u Aphidicolin(阿非科林，抗感染/抗病毒), Hydroxyurea(羟基脲)A panoply of DNA repair mechanisms maintains genomic stability.单链断裂 双链断裂错配/插入/缺失烷基化BER, base excision repair（碱基切除修复）; NER, nucleotide excision repair（核酸切除修复）;Homologous recombination:同源重组NHEJ, non-homologous end joining（非同源末端连接）;大量加合物Efficient repair of chemotherapy les