use of novel interstrand cross-linked DNA duplexes to investigate resistance to bifunctional alkylating chemotherapeutic agents

共价DNA损伤在癌症的治疗中起重要作用。在一些最古老的抗癌剂中，治疗性烷化剂可以是单官能或双官能的;后一类包括氮芥、氯乙基-亚硝基脲和甲基甲烷磺酸酯。这些试剂形成链间交联，如果不修复，则阻止DNA链分离和正常有丝分裂，干扰转录并诱导细胞凋亡。癌症治疗中存在的问题是对这些抗肿瘤剂的作用产生抗性，这通常是由于损伤的修复增强。我们的小组，通过合成和研究的寡核苷酸，含有模拟临床相关病变形成化疗期间，希望推进我们的理解，在其修复，一个重要的一步，阐明一些患者如何发展耐药性的影响，这些化疗药物的机制。

Covalent DNA lesions play important roles in the treatment of cancer. Therapeutic alkylating agents, among some of the oldest anti-cancer agents, may be monofunctional or bifunctional; the latter category includes nitrogen mustards, chloroethyl-nitrosoureas and methyl methane sulfonates. These agents form interstrand cross-links, which if left unrepaired, prevent DNA strand separation and normal mitosis, interfere with transcription and induce apoptosis. A problem presented in cancer treatment is the development of resistance to the effects of these antitumor agents, often due to enhanced repair of the damage. Our group, through the synthesis and investigation of oligonucleotides that contain mimics of clinically relevant lesions formed during chemotherapy, hopes to advance our understanding of the mechanisms involved in their repair, an important step towards elucidating how some patients develop resistance to the effects of these chemotherapeutic agents.