Kinzel V, Loehrke H, Goerttler K, Fürstenberger G, Marks F
Proc Natl Acad Sci U S A. 1984 Sep;81(18):5858-62. doi: 10.1073/pnas.81.18.5858.
In order to evaluate the significance of epidermal cell proliferation for the first stage of skin tumor promotion, the effect of hydroxyurea (HU), an inhibitor of DNA synthesis, on tumor formation was studied. Mice initiated with 7,12-dimethylbenz[a]anthracene received a single dose of phorbol 12-myristate 13-acetate (PMA) in stage I of promotion, followed by twice weekly application of the irritant skin mitogen phorbol 12-retinoate 13-acetate in stage II. A single dose of HU given intraperitoneally at different times before or after treatment with PMA was found to interfere with tumor formation, exhibiting an almost complete inhibition if administered 18 hr after PMA--i.e., at the time of maximal DNA synthesis. The inhibition of tumor formation by HU in the two-stage promotion experiment did not prevent a subsequent promotion of cells by repetitive PMA treatment. This indicates that the inhibitory effect of HU was due neither to cytotoxicity (killing of initiated cells) nor to an interference with initiation. The data indicate that epidermal DNA synthesis is obligatory for PMA-induced first-stage promotion. The causal relationship between both events remains to be established.
为了评估表皮细胞增殖在皮肤肿瘤促癌第一阶段的重要性，研究了DNA合成抑制剂羟基脲（HU）对肿瘤形成的影响。用7,12-二甲基苯并[a]蒽启动的小鼠在促癌第一阶段接受单剂量的佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA），随后在第二阶段每周两次应用刺激性皮肤有丝分裂原佛波醇12-视黄酸13-乙酸酯。发现在用PMA治疗之前或之后的不同时间腹腔注射单剂量的HU会干扰肿瘤形成，如果在PMA给药后18小时（即DNA合成最大时）给药，则表现出几乎完全抑制。在两阶段促癌实验中，HU对肿瘤形成的抑制作用并不妨碍随后通过重复PMA治疗对细胞的促癌作用。这表明HU的抑制作用既不是由于细胞毒性（杀死启动细胞），也不是由于对启动的干扰。数据表明，表皮DNA合成对于PMA诱导的第一阶段促癌是必不可少的。这两个事件之间的因果关系仍有待确定。
