FRIEDEWALD W F, ROUS P
J Exp Med. 1950 May 1;91(5):459-84. doi: 10.1084/jem.91.5.459.
The ears of young adult rabbits were painted with methylcholanthrene (MC) long enough to call forth a few benign tumors (papillomas, frill horns), and the animals were followed throughout their later lives. Soon after the paintings were stopped the tumors began to dwindle and vanished, yet even while they were disappearing other growths of the same kinds arose, only to vanish later in their turn. For a long while more arose than disappeared, and in consequence the number of tumors increased throughout years. They accumulated at a constant rate despite concurrent changes in the supporting skin, which might have been supposed, on previous experience, to have prevented this from happening. Only in the old age of the animals did the number of tumors eventually fall off, and by this time the skin on which they had arisen, long since normal in the gross to all appearance, had become nearly so microscopically. Even then latent neoplastic potentialities still existed in the cutaneous tissue; where punch holes were healing new tumors arose. A great multitude of hidden neoplastic cells were present in the MCed skin, and from them many of the growths called forth by the stimulus of healing undoubtedly derived. Yet the facts make it difficult to suppose that the long accumulation, at a constant rate, of tumors visible in the gross was due wholly to the proliferation of cells rendered neoplastic during the period of exposure to MC, and lying hidden afterwards for periods determined by their differing, evenly graded capabilities. Nor can the accumulation be attributed to a sustained carcinogenesis resulting from the pathological state of the skin. As a whole the findings indicate that the linear increase in growths was due for the most part to a continual arrival at the neoplastic state and subsequent proliferation of cells, or the descendants of cells, that had been no more than started on the way toward becoming neoplastic by the carcinogen. There is clinical evidence for such a course of events. Now and again a carcinoma arose from the skin previously treated with MC, but they were few in all, as would follow from the presence of local conditions unfavorable to malignant change. Some appeared only after years,-in one instance more than 5 years after. The occurrence of deferred cancer in man can be understood in terms of the findings in rabbits.
给成年幼兔的耳朵涂抹甲基胆蒽（MC）足够长的时间，以诱发一些良性肿瘤（乳头状瘤、皱襞角），并在它们随后的生命过程中对这些动物进行跟踪观察。在停止涂抹后不久，肿瘤开始缩小并消失，但即使在它们消失的同时，又出现了其他同类肿瘤，只是随后也依次消失了。在较长一段时间内，出现的肿瘤比消失的多，因此多年来肿瘤的数量一直在增加。尽管支持肿瘤生长的皮肤同时发生了变化，但根据以往经验，这些变化本应阻止这种情况发生，但肿瘤仍以恒定的速率累积。只有在动物年老时，肿瘤的数量最终才会减少，此时肿瘤生长的皮肤在肉眼看来早已恢复正常，在显微镜下也几乎如此。即便如此，皮肤组织中仍然存在潜在的肿瘤形成潜能；在打孔愈合的地方会出现新的肿瘤。在涂抹过MC的皮肤中存在大量隐藏的肿瘤细胞，无疑，许多由愈合刺激引发的肿瘤都源自这些细胞。然而，这些事实让人难以认为，肉眼可见的肿瘤以恒定速率长期累积完全是由于在接触MC期间变成肿瘤性的细胞增殖，这些细胞随后隐藏起来，其持续时间取决于它们不同的、均匀分级的能力。这种累积也不能归因于皮肤病理状态导致的持续致癌作用。总体而言，这些发现表明，肿瘤数量的线性增加在很大程度上是由于不断有细胞或细胞后代进入肿瘤状态并随后增殖，这些细胞或细胞后代只是被致癌物启动了向肿瘤状态发展的进程而已。有临床证据支持这样的事件过程。偶尔会有癌从先前用MC处理过的皮肤中发生，但总体数量很少，这是因为存在不利于恶性变化的局部条件。有些癌几年后才出现，有一个例子是在5年多以后出现的。人类中延迟性癌症的发生可以根据兔子的研究结果来理解。
