Spanswick V J, Hartley J M, Ward T H, Hartley J A
CRC Drug-DNA Interactions Research Group, Department of Oncology, University College London Medical School, London, UK.
Methods Mol Med. 1999;28:143-54. doi: 10.1385/1-59259-687-8:143.
DNA damaging agents have been widely used in cancer chemotherapy for many years and have proved successful in the treatment of both solid tissue and haematological malignancies. Many commonly used clinical agents, such as members of the nitrogen mustard, chloroethylnitrosourea, dimethane-sulphonate and platinum classes, are bifunctional. DNA interstrand crosslinks (ISC) formed in cells are clearly critical cytotoxic lesions and the formation of DNA ISC has been shown to correlate with cytotoxicity in vitro (1-5). Acquired resistance in vitro to such agents can occur by a number of mechanisms, for example altered drug transport (6), intracellular detoxification via enhanced glutathione and glutathione-S-transferase activity (7), but enhanced DNA repair capacity can also play an important role (3). Clinically the mechanisms of acquired resistance to DNA damaging agents are less clear but enhanced repair of ISC has been suggested to play a role in the acquired resistance of some cancers, e.g., chronic lymphocytic leukaemia to nitrogen mustards (8). In addition, the inherent sensitivity (and curability) of some tumors, e.g., testicular cancer, to DNA damaging agents may result in part from their inability to repair critical DNA lesions (9).
多年来，DNA损伤剂已广泛应用于癌症化疗，并已证明在实体组织和血液系统恶性肿瘤的治疗中取得成功。许多常用的临床药物，如氮芥、氯乙基亚硝脲、二甲烷磺酸盐和铂类药物的成员，都是双功能的。细胞中形成的DNA链间交联（ISC）显然是关键的细胞毒性损伤，并且已证明DNA ISC的形成与体外细胞毒性相关（1-5）。体外对这类药物获得性耐药可通过多种机制发生，例如药物转运改变（6）、通过增强谷胱甘肽和谷胱甘肽-S-转移酶活性进行细胞内解毒（7），但增强的DNA修复能力也可发挥重要作用（3）。临床上，对DNA损伤剂获得性耐药的机制尚不清楚，但有人提出ISC修复增强在某些癌症的获得性耐药中起作用，例如慢性淋巴细胞白血病对氮芥的耐药（8）。此外，一些肿瘤，如睾丸癌，对DNA损伤剂的固有敏感性（和可治愈性）可能部分源于它们无法修复关键的DNA损伤（9）。
