Bignold Leon P
Institute of Medical and Veterinary Science, Adelaide, SA 5001, Australia.
Anticancer Res. 2006 Mar-Apr;26(2B):1327-36.
Alkylating agents, for example nitrogen "mustards", are variably toxic, mutagenic, carcinogenic and teratogenic, but by mechanisms which have not been clearly established. In particular, the mechanisms both of their delayed toxic effects (which are primarily against dividing cells, in association with retardation of the rate of cell division, disruption of mitoses, and breakages and other abnormalities of chromosomes) and of their carcinogenic actions are not understood. The literature on the testing of thousands of analogues has demonstrated great variability of effects on the various cell biological phenomena, and no aspect of chemical structure or biochemical reactivity of these agents has been established as especially related to any particular effect. Here theories of the mechanisms of action of alkylating agents are reviewed and it is suggested that impairment of the functions of DNA polymerase complexes might contribute to some of the effects of alkylating agents. In particular, impairment of replicative fidelity of DNA during the S-phase could contribute to some of the mitotic and chromosomal effects, as well as to their carcinogenic and teratogenic potencies. Some aspects of testing the effects of alkylating agents on components of the DNA synthetic pathway are mentioned. Emphasis is given to consideration of the various relevant levels (conventional plasma/tissue; tissue/tumour cell cytoplasm; tumour cell cytoplasm/tumour cell nucleus and tumour nuclear karyoplasm/tumour chromatin] of the pharmacokinetics and pharmacodynamics of the agents and their metabolites.
烷化剂，例如氮“芥”，具有不同程度的毒性、致突变性、致癌性和致畸性，但其作用机制尚未明确确立。特别是，它们的延迟毒性作用（主要针对分裂细胞，伴随着细胞分裂速率的减缓、有丝分裂的破坏以及染色体的断裂和其他异常）和致癌作用的机制尚不清楚。关于数千种类似物的测试文献表明，这些物质对各种细胞生物学现象的影响差异很大，而且这些试剂的化学结构或生化反应性的任何方面都未被确定与任何特定效应特别相关。本文综述了烷化剂的作用机制理论，并提出DNA聚合酶复合物功能的损害可能是烷化剂某些效应的原因。特别是，S期DNA复制保真度的损害可能导致一些有丝分裂和染色体效应，以及它们的致癌和致畸潜能。文中还提到了测试烷化剂对DNA合成途径成分影响的一些方面。重点是考虑这些试剂及其代谢产物在药代动力学和药效学方面的各种相关水平（传统血浆/组织；组织/肿瘤细胞质；肿瘤细胞质/肿瘤细胞核以及肿瘤核质/肿瘤染色质）。
