Iversen O H
Institute of Pathology, University of Oslo, Norway.
APMIS Suppl. 1994;41:1-38.
A carcinogen has recently been defined as an agent that causes a neoplasm by a two-step process involving initiation and promotion. The difference between the two steps is said to be qualitative rather than quantitative. According to this theory, the hydrocarbon carcinogen, 7,12-dimethylbenz-alpha-anthracene (DMBA) has both initiating and promoting properties, and it has been claimed that when the dose level is lowered, the promoting activity is first reduced while its initiating activity is retained, until at a small dose even the promoting property has completely disappeared, and only the initiating property remains. The theory also says, however, that for carcinogens individual doses are additive, and for pure initiators individual doses are additive even at subthreshold doses. Promoters are said to act in a synergistic way on initiated skin, and a threshold exists below which there is no effect. Experiments were carried out to test the validity of these claims. DMBA was applied twice a week in very small (10 or 4 nmol) doses to the skin of hairless mice, with or without previous initiation. When, after DMBA initiation, DMBA or 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were applied twice a week at small equimolar doses, a real synergistic effect, said to characterize promotion, was obtained with DMBA also, and with an even higher tumor crop and many more carcinomas than those elicited by TPA. Promotion with repeated doses of 10 nmol DMBA resulted in very significantly more carcinomas than with 4 nmol DMBA, which again gave more carcinomas than promotion with 10 nmol TPA. Repeated doses of TPA alone gave a 9% tumor rate, and TPA is thus a complete carcinogen. Reverse experiments were not innocuous. These results contradict the hypothesis that very small doses of DMBA have only initiating properties with only additive and not synergistic effects, and that TPA is only a promoter. It is most probable that the difference between the tumorigenic and carcinogenic effects of DMBA and TPA is not qualitative, but quantitative. TPA is highly toxic; it induces cell death followed by pronounced regeneration, and even DNA alterations. It is a complete, but weak carcinogen. DMBA is a strong complete carcinogen, binding covalently to DNA and altering it in various ways, but in equimolar doses it is less acutely toxic than TPA.(ABSTRACT TRUNCATED AT 400 WORDS)
致癌物最近被定义为一种通过涉及启动和促进的两步过程导致肿瘤形成的物质。据说这两个步骤之间的差异是质的而非量的。根据这一理论，烃类致癌物7,12 - 二甲基苯并[a]蒽（DMBA）兼具启动和促进特性，并且有人声称当剂量水平降低时，促进活性首先降低而其启动活性得以保留，直到在小剂量时甚至促进特性完全消失，仅保留启动特性。然而，该理论还指出，对于致癌物，个体剂量是可加性的，而对于纯启动剂，即使在阈下剂量个体剂量也是可加性的。促进剂据说对已启动的皮肤起协同作用，并且存在一个阈值，低于该阈值则无效应。进行了实验以检验这些说法的有效性。将DMBA以非常小的（10或4纳摩尔）剂量每周两次施用于无毛小鼠的皮肤，有无预先启动均可。在DMBA启动后，当以小的等摩尔剂量每周两次施用DMBA或12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）时，与TPA一样，DMBA也获得了一种真正的协同效应，据说这是促进作用的特征，并且与TPA引发的相比，肿瘤产量更高且癌更多。用10纳摩尔DMBA重复给药促进产生的癌比用4纳摩尔DMBA显著更多，而4纳摩尔DMBA产生的癌又比用10纳摩尔TPA促进产生的更多。单独重复给予TPA产生9%的肿瘤发生率，因此TPA是一种完全致癌物。反向实验并非无害。这些结果与以下假设相矛盾：非常小剂量的DMBA仅具有启动特性，仅具有可加性而非协同效应，并且TPA仅是一种促进剂。很可能DMBA和TPA的致瘤和致癌作用之间的差异不是质的，而是量的。TPA具有高毒性；它诱导细胞死亡随后是明显的再生，甚至导致DNA改变。它是一种完全但较弱的致癌物。DMBA是一种强完全致癌物，与DNA共价结合并以各种方式改变它，但在等摩尔剂量下它的急性毒性比TPA小。（摘要截短于400字）
