Early effects of 12-O-tetradecanoyl-phorbol-13-acetate on the incorporation of tritiated precursor into DNA and the thickness of the interfollicular epidermis, and their relation to tumor promotion in mouse skin.
Early effects of 12-O-tetradecanoyl-phorbol-13-acetate on the incorporation of tritiated precursor into DNA and the thickness of the interfollicular epidermis, and their relation to tumor promotion in mouse skin.
复制标题
12-O-十四酰佛波醇-13-乙酸酯对氚化前体掺入 DNA 和毛囊间表皮厚度的早期影响，及其与小鼠皮肤肿瘤促进的关系。
作者：
A. Raick;K. Thumm;B. R. Chivers
研究了不同剂量12- O -十四烷醇-13-乙酸酯（TPA）对小鼠皮肤的宏观和组织学改变；测定其致瘤活性和促瘤活性，并测定其对卵泡间表皮（IFE）厚度和胸腺嘧啶-甲基- 3h入皮肤DNA率的影响。TPA在0.016 ~ 0.0016 emole剂量范围内具有明显的促进活性，而在0.00016 emole剂量范围内则没有，提示在0.0016 ~ 0.00016 emole之间存在促进活性的阈值。0.08和0.16摩尔的TPA剂量会引起皮肤明显的坏死和溃疡，因此不适合研究促肿瘤活性。胸苷-甲基- 3h并入DNA的速率和IFE厚度的变化在程度和持续时间上呈剂量依赖性。TPA的单次应用最初会抑制胸腺嘧啶-甲基- 3h与DNA的结合，随后显著刺激结合率，此后恢复到控制水平。在第一次应用TPA后168小时，第二次应用TPA后，未观察到胸腺嘧啶-甲基- 3h并入DNA的初始抑制，并且掺入率增加的开始时间更早，其峰值更高。单次应用TPA诱导IFE厚度显著增加，但在120至168小时后恢复到对照水平。第二次应用后，IFE的厚度增加了1.5 ~ 2.0倍，厚度峰值比单次应用更早到达，表明TPA的第一次应用增强了后续应用的效果。TPA浓度分别为0.016和0.0016 emole时，IFE厚度的增加与皮肤肿瘤的促进存在相关性。然而，0.00016 emole TPA诱导IFE厚度和胸苷-甲基- 3h并入DNA的速率显著增加，但不表现出促进活性，说明表皮增生的阈值与促进活性的阈值不同，提示增生性作用和促进作用是独立的现象。
The macroscopic and histological changes induced in mouse skin by various doses of 12- O -tetradecanoyl-phorbol-13-acetate (TPA) were studied; its tumorigenic and tumorpromoting activity were tested, and the changes induced in the thickness of interfollicular epidermis (IFE) and in the rate of incorporation of thymidine-methyl-3H into skin DNA were measured. TPA in the dose range of 0.016 to 0.0016 emole shows marked promoting activity, while 0.00016 emole does not, thus suggesting a threshold for promoting activity between 0.0016 and 0.00016 emole. Doses of 0.08 and 0.16 emole of TPA induce marked necrosis and ulceration of the skin and are therefore unsuitable for studies of tumor-promoting activity. The changes in the rate of incorporation of thymidine-methyl-3H into DNA and the thickness of IFE are dose dependent in degree and duration. A single application of TPA induces initially an inhibition in the incorporation of thymidine-methyl-3H into DNA, followed by marked stimulation in the rate of incorporation and returning to control levels thereafter. Following a second application of TPA, 168 hr after the first, the initial inhibition of thymidine-methyl-3H incorporation into DNA is not observed, and the onset of the increase in the rate of incorporation is earlier and its peak is higher. A single application of TPA induces a marked increase in the thickness of IFE, but this reverts to the control level between 120 and 168 hr later. After a second application, the increase in the thickness of IFE is 1.5 to 2.0 times higher, and the peak of thickness is reached earlier than after a single application, suggesting that the first application of TPA potentiates the effects of subsequent applications. There is a correlation between the increase in thickness of IFE and skin tumor promotion with 0.016 and 0.0016 emole of TPA. However, 0.00016 emole of TPA induces a significant increase in the thickness of IFE and in the rate of incorporation of thymidine-methyl-3H into DNA but does not show promoting activity, indicating that the threshold for epidermal hyperplasia is different from that for promoting activity and suggesting that hyperplastic action and promoting action are independent phenomena.