Craddock V M
Chem Biol Interact. 1975 May;10(5):323-32. doi: 10.1016/0009-2797(75)90053-8.
Experiments were carried out to determine whether replication of alkylated DNA could be involved in the initiation of hepatocellular carcinoma which results from a single administration of dimethylnitrosamine (DMN) given after partial hepatectomy. The incidence of tumours is higher when DMN is given during the wave of DNA synthesis induced by the operation than when given in the early prereplicative stage. Therefore the alkylation of DNA in the regenerating liver by DMN given at these times and the effect of DMN on DNA synthesis were investigated. The extent, duration and pattern of alkylation of DNA, including the formation of 0-6-methylguanine, were similar whether DMN was given in the early pre-replicative stage (6 h after the operation) or during the period of DNA synthesis (at 24 h). DMN given a 6 h very greatly reduced the wave of DNA replication which would otherwise have ensued. When given at 24 h, by which time DNA synthesis was already taking place, DMN reduced the rate of incorporation of (-3H)thymidine after 1-2 h delay. However, in neither case was DNA synthesis reduced to the level occurring in normal intact liver. Treatment with diethylnitrosamine (DEN) at 6 h or at 24 h had a similar effect to DMN on the wave of DNA replication induced by partial hepatectomy. Methyl methanesulphonate (MMS given in the early pre-replicative stage delayed the wave of DNA synthesis by about 8 h, but when it did take place the extent of synthesis was as great as in untreated animals. When given during the period of DNA replication, MMS rapidly reduced the rate of synthesis. As in the case of the nitrosamines, synthesis was not reduced to the level occuring in normal intact animals. The difference from the nitrosamines lies in the nature of the alkylated bases formed in DNA. The fact that a single treatment with DMN induces cancer in partially hepatectomised animals but not in intact adult animals is not considered to be due to a gross difference in the nature of the alkylation of DNA. The experiments described support the concept that replication of DNA containing bases which are likely to mispair during replication may be necessary to 'fix' the lesion and thus cause a permanent inheritable change in the genetic material.
进行了实验以确定烷基化DNA的复制是否可能参与了肝细胞癌的起始过程，该过程源于在部分肝切除术后单次给予二甲基亚硝胺（DMN）。当在手术诱导的DNA合成期给予DMN时，肿瘤发生率高于在复制前期早期给予时。因此，研究了此时DMN对再生肝中DNA的烷基化作用以及DMN对DNA合成的影响。无论DMN是在复制前期早期（手术后6小时）还是在DNA合成期（24小时）给予，DNA烷基化的程度、持续时间和模式，包括0-6-甲基鸟嘌呤的形成，都是相似的。在6小时给予DMN极大地减少了原本会随之而来的DNA复制波。在24小时给予时，此时DNA合成已经发生，DMN在延迟1-2小时后降低了（-3H）胸腺嘧啶核苷的掺入率。然而，在这两种情况下，DNA合成都没有降低到正常完整肝脏中的水平。在6小时或24小时用二乙基亚硝胺（DEN）处理对部分肝切除诱导的DNA复制波有与DMN类似的作用。在复制前期早期给予甲磺酸甲酯（MMS）使DNA合成波延迟约8小时，但当合成发生时，合成程度与未处理动物一样大。在DNA复制期给予时，MMS迅速降低了合成速率。与亚硝胺的情况一样，合成没有降低到正常完整动物中的水平。与亚硝胺的差异在于DNA中形成的烷基化碱基的性质。单次用DMN处理在部分肝切除的动物中诱导癌症，但在完整成年动物中不诱导，这一事实不被认为是由于DNA烷基化性质的显著差异。所述实验支持这样的概念，即含有在复制过程中可能错配的碱基的DNA的复制可能是“固定”损伤从而导致遗传物质发生永久性可遗传变化所必需的。
