Bremner R, Kemp C J, Balmain A
Beatson Institute for Cancer Research, Wolfson Laboratory for Molecular Pathology, Glasgow, United Kingdom.
Mol Carcinog. 1994 Oct;11(2):90-7. doi: 10.1002/mc.2940110206.
By analysis of skin tumors from F1 hybrid mice we demonstrated that the genetic events that occur during tumor progression depend on the type of chemical carcinogenesis protocol used to induce tumor growth. More than 95% of tumors induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) exhibited mutations in Ha-ras and trisomy of chromosome 7. Carcinomas induced with multiple DMBA treatments had a lower frequency of alterations on chromosome 7 (50%), but only in tumors with Ha-ras mutations, and had a much wider spectrum of alterations, including trisomy, mitotic recombination, deletion, and gene duplication. Carcinomas induced with multiple N-methyl-N'-nitro-N-nitrosoguanidine treatments only rarely exhibited alterations on chromosome 7 (8%), even if they contained mutant Ha-ras. More frequent numerical alterations of chromosome 11 were also seen in TPA-promoted tumors (23%) than in tumors induced by multiple carcinogen treatments (8%). These results show that postinitiation events are nonrandom and fit a model in which promoting agents induce numerical chromosomal alterations but in which mutagens cause more directed mutational events.
通过对F1杂交小鼠皮肤肿瘤的分析，我们证明了肿瘤进展过程中发生的基因事件取决于用于诱导肿瘤生长的化学致癌方案的类型。超过95%由7,12-二甲基苯并[a]蒽（DMBA）启动并用12-O-十四烷酰佛波醇-13-乙酸酯（TPA）促进诱导的肿瘤在Ha-ras基因中发生突变并出现7号染色体三体性。多次DMBA处理诱导的癌在7号染色体上的改变频率较低（50%），但仅在具有Ha-ras突变的肿瘤中如此，并且具有更广泛的改变谱，包括三体性、有丝分裂重组、缺失和基因复制。多次N-甲基-N'-硝基-N-亚硝基胍处理诱导的癌即使含有突变的Ha-ras，也很少在7号染色体上出现改变（8%）。在TPA促进的肿瘤中（23%）也比在多次致癌物处理诱导的肿瘤中（8%）更频繁地观察到染色体11的数目改变。这些结果表明，启动后事件是非随机的，符合一种模型，即促进剂诱导染色体数目改变，而诱变剂导致更具针对性的突变事件。
