Hall A G, Tilby M J
Leukaemia Research Fund Remission Unit, Medical School, Framlington Place, Newcastle upon Tyne, UK.
Blood Rev. 1992 Sep;6(3):163-73. doi: 10.1016/0268-960x(92)90028-o.
Although the alkylating agents were amongst the first non-hormonal compounds to be shown to be active against malignant cells they still rank as some of the most valuable cytotoxic drugs available for the treatment of patients with leukaemia and lymphoma. Melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide and the nitrosoureas are all members of this class of drug, which are believed to exert their cytotoxic effects through the covalent linkage of alkyl groups to DNA. In the first report describing the use of alkylating agents in clinical practice the problem of drug resistance was recognised. In spite of this there is still comparatively little known about the mechanisms underlying the development of resistance as it occurs in patients. Studies using animal models and cell lines have suggested that both cellular and extracellular factors may be involved, but the precise relevance of these to the clinical setting is unclear. A greater understanding of the mode of action and mechanisms of resistance to alkylating agents should enable the development of modulators capable of the restoration of sensitivity to resistant cells, and the more effective use of these well established drugs.
尽管烷化剂是最早被证明对恶性细胞有活性的非激素化合物之一，但它们仍然是可用于治疗白血病和淋巴瘤患者的一些最有价值的细胞毒性药物。美法仑、苯丁酸氮芥、白消安、环磷酰胺、异环磷酰胺和亚硝基脲都是这类药物的成员，据信它们通过烷基与DNA的共价连接发挥细胞毒性作用。在描述烷化剂临床应用的第一份报告中，就认识到了耐药性问题。尽管如此，对于患者出现耐药性的潜在机制仍知之甚少。使用动物模型和细胞系的研究表明，细胞和细胞外因素可能都参与其中，但它们与临床情况的确切相关性尚不清楚。对烷化剂的作用方式和耐药机制有更深入的了解，应该能够开发出能够恢复耐药细胞敏感性的调节剂，并更有效地使用这些成熟的药物。
