Current Concepts of Tumor Promotion by Phorbol Esters and Related Compounds
Studies of carcinogenesis on mouse skin have shown that the mechanism of carcinogenesis clearly involves at least two qualitatively distinct stages (Weinstein, 1981a; Weinstein et al., 1982, and references therein). Initiation, the first stage in the two-stage model, is rapid and apparently irreversible. The observed molecular actions of initiators appear to be rapid and irreversible, since several initiators of carcinogenesis or their metabolites are electrophiles that covalently modify DNA in vivo. The second stage, promotion, is a slow and often reversible process during which initiated cells become neoplastic. Promotion is also distinguished from initiation at the molecular level, since certain tumor promoters do not bind covalently to cellular DNA but do bind reversibly to cell membrane receptors. The two-stage mouse skin carcinogenesis model has been used as a paradigm for studies on multistage carcinogenesis in several other systems. Evidence that hepatocellular cancer, bladder cancer, colon cancer, and breast cancer also proceed via processes analogous to initiation and promotion has been reviewed elsewhere (Slaga et al., 1978; Weinstein et al., 1981b). The concept of promotion appears to be especially relevant to an understanding of the causation of human breast cancer (Weinstein et al., 1981b).
KeywordsPhorbol Ester Tumor Promoter Indole Alkaloid Multistage Carcinogenesis Human Mammary Carcinoma Cell
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