Kinzel V, Färber B, Petrusevska R T, Fusenig N
Institute of Experimental Pathology, German Cancer Research Center, Heidelberg.
Prog Clin Biol Res. 1990;340D:133-41.
The conversion step of multistage tumorigenesis in mouse skin effected by TPA (12-O-tetradecanoylphorbol-13-acetate) but not by RPA (12-O-retinoylphorbol-13-acetate) may be best explained by the clastogenic (and mitogenic) activity of TPA. In mouse keratinocytes in vitro as well as in vivo TPA (but not RPA) was shown earlier to induce a significant degree of chromosomal aberrations. Details of the clastogenic action of TPA were studied in HeLa cells. Only TPA exerted a significant clastogenic activity at non-cytotoxic concentrations (10(-8) to 10(-6) M) measured after 24 and 48 hrs. Values obtained with RPA were close to those obtained in the presence of solvent (acetone 0.2%). The response to TPA was only to some extent correlated with the dose. Chromosomal aberrations including gaps and breaks were predominantly of the chromatid type; they are first measurable after 6-8 hrs, i.e. as soon as the cells recover from TPA-induced G2-inhibition. A 30 min exposure to TPA (10(-7) M) is sufficient to induce aberrations. The data point to an indirect, possibly receptor-mediated action of TPA. Supposing that TPA-induced chromosomal lesions represent a key event required for conversion, it is suggested that the absolute requirement for DNA replication in the conversion step is necessary to "fix" a certain degree of chromosomal damage. Therefore, the clastogenic as well as the mitogenic activity of TPA appear to be necessary for effecting conversion.
佛波酯（12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯，TPA）而非视黄酸佛波酯（12 - O - 视黄酰佛波醇 - 13 - 乙酸酯，RPA）所影响的小鼠皮肤多阶段肿瘤发生的转化步骤，或许可用TPA的致断裂（及促有丝分裂）活性来最好地解释。先前已表明，在体外及体内的小鼠角质形成细胞中，TPA（而非RPA）可诱导显著程度的染色体畸变。在HeLa细胞中研究了TPA的致断裂作用细节。仅TPA在24小时和48小时后测量的非细胞毒性浓度（10⁻⁸至10⁻⁶M）下发挥显著的致断裂活性。RPA获得的值与在溶剂（0.2%丙酮）存在下获得的值相近。对TPA的反应仅在一定程度上与剂量相关。包括间隙和断裂在内的染色体畸变主要为染色单体型；它们在6 - 8小时后首次可测，即细胞一旦从TPA诱导的G2期抑制中恢复。暴露于TPA（10⁻⁷M）持续30分钟足以诱导畸变。数据表明TPA存在间接的、可能是受体介导的作用。假设TPA诱导的染色体损伤代表转化所需的关键事件，那么有人提出在转化步骤中对DNA复制的绝对需求对于“固定”一定程度的染色体损伤是必要的。因此，TPA的致断裂及促有丝分裂活性似乎对于实现转化是必要的。
