As noted above, the primary characteristic of the promotion stage seen in models of cancer de- velopment is its operational reversibility (Williams and Watanabe, 1978; Iversen, 1982; Moore et al., 1983; Hill et al., 1989). Several examples of the reversibility of human preneoplasia are provided in Table 7.12. Lung cancer risk has been reported to decrease exponentially with the time after cessation of smoking. After 15 to 20 years of nonsmoking, the risk of lung cancer in the smokers that stopped smoking was essentially equivalent to that for nonsmokers (cf. Reif,1981). In addition, Zatonski et al. (1990) demonstrated a dramatic decrease in the risk of laryn- geal cancers in smokers who had stopped smoking, as well as in those who stopped smoking for 1 to 4 years but then resumed the habit. This last finding is very similar to the lessened effect of intermittent compared with continual exposure to a promoting agent on the subsequent yield of preneoplastic lesions (Boutwell, 1964; Xu et al., 1991). In addition, atypical epithelial hyperpla- sia of the oral cavity seen in tobacco users disappears upon cessation of tobacco product use (Table 7.12). Furthermore, the administration of retinoids can also lead to the reversible disap- pearance of oral leukoplakia (Hong et al., 1986).
Several other organ systems also exhibit preneoplastic lesions that regress under some conditions. For example, preneoplastic lesions of the stomach and colon display an instability based on their regression with or without intervention (Table 7.12). In addition, chemopreventive trials with nonsteroidal anti-inflammatory agents have demonstrated a regression of the polyps that are believed to be precursors to colonic adenocarcinomas (Giardiello et al., 1993). Perhaps the clearest example of regression of a human preneoplastic lesion is that of regression of nodu- lar hyperplasia and adenomas of the liver induced by administration of some synthetic estrogen preparations to premenopausal women (Edmondson et al., 1977; Steinbrecher et al., 1981; Bühler et al., 1982). Most of these lesions disappeared upon cessation of use of these contracep- tive preparations (Table 7.12).
Thus, it is apparent that the stages of initiation and promotion, including the major charac- teristic of the latter, operational reversibility, can be demonstrated in the human. Thus, it is likely that the genesis of many if not the majority of human neoplasms may involve the stages of initi- ation and promotion, accounting not only for the extensive known latent period in the develop- ment of human neoplasia (Chapter 11) but also the effects of a variety of chemopreventive (Chapter 8) agents acting during the stage of promotion to prevent further development of the neoplastic process.