STAGES OF INITIATION AND PROMOTION AS GENERAL CHARACTERISTICS OF CARCINOGENESIS

27 May

As indicated above, the initial studies of the basis for the latency of neoplastic development were carried out primarily in the mouse epidermis. Later studies by Foulds and others (Foulds, 1949; Medina, 1976) on the intermediate lesions occurring during the development of mammary ade- nocarcinomas in the mouse represented another system for the study of neoplastic development, but the initial emphasis was on the fate of early lesions rather than on the entire process. Within the last two decades, the development of a number of different histogenetic neoplasms in a vari- ety of species has been investigated and found to have characteristics very similar to those origi- nally described in the mouse epidermis model. Table 7.1 lists many of the animal systems in

Key: Abbreviations  used in this table are as follows: MNU, N-methyl-N-nitrosourea; FANFT, N[4-(5-Nitro-2-furyl)-2- thiazoly]formamide; BBN, N-butyl N-(4-hydroxybutyl) nitrosamine; BHA, butylated  hydroxyanisole; MNNG, N-methyl-N1-nitro-N-nitrosoguanidine; 1,2-DMH,  dimethylhydrazine; TPA, tetradecanoyl  phorbol acetate; 3-MC,3-methylcholanthrene; BP, benzo[a]pyrene; 1,25-(OH)2-D2,  1α,25-dihydroxycholecalciferol; DMBA, 7,12-dimethyl- benzanthracene; 7-BrMeBA, 7-bromomethyl benzanthracene; TEM, triethylene melamine; Trp-P-2, 3-Amino-1-methyl-5H-pyrido[4,3-b]-indole; AMN, N-amyl-N-methylnitrosamine; AAF, 2-acetylaminofluorene; DEN, diethylnitrosamine; DMN, dimethylnitrosamine; DAB, dimethylaminoazobenzene; NNM, N-nitrosomorpholine; αHCH, αhexachloro- cyclohexane;  PenCDF,  2,3,4,7,8-pentachlorodibenzofuran; CPA, cyproterone  acetate; PB, phenobarbital;  TCDD,2,3,7,8-tetrachlorodibenzo-p-dioxin; DDT, dichlorodiphenyltrichloroethane; BHT, butylated  hydroxytoluene; DCA, deoxycholic  acid; DEHP, di(2-ethylhexyl)-phthalate; TCPOBOP,  1,4-bis[2-(3,5-dichloropyridyloxy)]benzene; 4NQO,4-nitroquinoline-1-oxide; NMU, N-nitrosomethylurea; HAQO, 4-hydroxyaminoquinoline 1-oxide; DHPN, N-bis(2- hydroxypropyl)nitrosamine; AT, 3-amino-1,2,4-triazole; EPH, 5-ethyl-5-phenylhydantoins; AOM, azoxymethane; PB, phenobarbital.

Modified from Pitot, 1996, with permission of the publisher.

which the stages of initiation and promotion may be identified. The exact characteristics of the stages in different tissues may vary somewhat with the experimental conditions and as a result of the biology of the system itself. There is also substantial evidence for the existence of the stages of initiation and promotion in the development  of a number of human neoplasms, considered later (Chapter 11).

In Table 7.1, most of the end-point lesions induced are malignant neoplasms. However, the development of malignancy implies that the final stage, progression, in which cancer develops (Chapter 9) has also occurred. Thus, strictly speaking, a study of the stages of initiation and promotion  should be restricted  to the development  of preneoplastic lesions that have distinct characteristics  (see below) distinguishing  them from malignant neoplasms.  Preneoplasia thus may be defined as lesions in the stage of initiation and/or promotion, while neoplastic lesions are restricted to those in the stage of progression (Chapters 9 and 10). Although it has not been possible to identify preneoplastic  lesions in the genesis of all neoplasms listed in Table 7.1, a large number of putative preneoplastic lesions have been described in animal carcinogenesis. A number of these are listed in Table 7.2. Most of the examples in Table 7.2 may be found in Table 7.1 as examples of two-stage carcinogenesis. As discussed in Chapter 10, many of these preneo- plastic lesions in rodents have their counterparts in the development of neoplasia in the human.

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