Dzarlieva-Petrusevska R T, Fusenig N E
Carcinogenesis. 1985 Oct;6(10):1447-56. doi: 10.1093/carcin/6.10.1447.
The effect of the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on the induction of numerical and structural chromosomal aberrations, double minute chromosomes (DM) and homogeneously staining regions (HSR) was investigated in two mouse keratinocyte cell lines (HEL-30 and HEL-37) using G- and C-banded chromosomal preparations. The frequency of polyploid metaphases and of structural aberrations increased several fold during the first two cell cycles. The increase of gaps, chromatid and isochromatid breaks was accompanied by inter- and intrachromosomal exchanges, which were virtually absent in control cultures. The induction of chromosomal aberrations was similarly expressed in both cell lines at different passage levels and was largely independent of the TPA dose applied (10(-9) - 10(-6) M). The non-promoting phorbolester 4-O-methyl-TPA (10(-6) M) did not produce any chromosomal aberrations above the control level. Effects were already visible within one cell cycle (24 h) after treatment and increased with longer and multiple exposure. Moreover, the TPA-induced chromosomal aberrations persisted for several days after elimination of the promoter and further cultivation of cells in fresh medium. Structural alterations were not randomly distributed but chromosomes 1 and 2 were preferentially involved in breaks, while chromosomes 1-3 and 9-13 were mainly involved in chromosomal exchanges. Chromosomes 7 and 14, which are numerically underrepresented in HEL cells, were least involved in breaks. Most interesting, the frequency of metaphases carrying DMs increased 2- to 3-fold after TPA treatment, and the alterations were partially reversible after removal of TPA. These early effects of TPA at the chromosomal level could play an essential role in the mechanism of tumor promotion and may be responsible for the observed persistence of alterations induced during the first stage of tumor promotion.
利用G带和C带染色体标本，在两种小鼠角质形成细胞系（HEL - 30和HEL - 37）中研究了肿瘤启动子十四酰佛波醇乙酯（TPA）对数值和结构染色体畸变、双微体染色体（DM）及均匀染色区（HSR）诱导作用。在前两个细胞周期中，多倍体中期和结构畸变的频率增加了几倍。间隙、染色单体和等染色单体断裂的增加伴随着染色体间和染色体内的交换，而在对照培养物中几乎不存在这种情况。在不同传代水平的两种细胞系中，染色体畸变的诱导情况相似，且在很大程度上与所应用的TPA剂量（10⁻⁹ - 10⁻⁶ M）无关。非促癌佛波酯4 - O - 甲基 - TPA（10⁻⁶ M）在对照水平以上未产生任何染色体畸变。处理后一个细胞周期（24小时）内效应已可见，且随着更长时间和多次暴露而增加。此外，在去除启动子并在新鲜培养基中进一步培养细胞后，TPA诱导的染色体畸变持续了数天。结构改变并非随机分布，1号和2号染色体优先参与断裂，而1 - 3号和9 - 13号染色体主要参与染色体交换。在HEL细胞中数量较少的7号和14号染色体最少参与断裂。最有趣的是，TPA处理后携带双微体的中期细胞频率增加了2至3倍，并且在去除TPA后这些改变部分可逆。TPA在染色体水平的这些早期效应可能在肿瘤促进机制中起重要作用，并且可能是肿瘤促进第一阶段诱导的改变持续存在的原因。
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