Preneoplastic cells

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

The nature of a preneoplastic cell in vitro is not defined clearly and, therefore, it is difficult to discriminate between normal and preneoplastic cells. Some aneuploid cell lines have been demonstrated as preneoplastic by their increased propensity to become neoplastic in vitro and in vivo (Barrett et al, 1984). For this reason, it is assumed that only early-passage, diploid cells are normal and that all aneuploid cell lines are preneoplastic. Whether establishment as a permanent cell liner per se is a preneoplastic alteration is unclear, especially if the cells remain diploid, an event which occurs only rarely. 

Preneoplastic cells, that is, those which have been initiated and which are selectively proliferated, may have altered mechanisms of cell cycle control. However, this selective enhancement of the cell cycle in initiated cells is not understood. 

Selenium, at 5 X10 M, stimulated the growth of primary cell cultures of normal mammary cells and C4 preneoplastic cells and the established cell line YN-4 but not the growth of D2 preneoplastic cells and tumors in primary cell cultures and of established cell lines CL-S1 and Waz-2t. The differential response of cells from preneoplastic outgrowth lines C4 and D2 and of D2 primary tumors in vitro correlated with the sensitivity of these same cell populations to selenium mediated inhibition of growth and tumorigenesis in vivo. Selenium had little effect on 3 or 4 preneoplastic mammary outgrowth lines. Recent studies by Poirier et al., (70) have shown that... 

G14. Grasl-Kraupp, B., Bursch, W., Ruttkay-Nedecky, A., Wagner, A., Lauer, B., and Schulte-Herman, R., Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver. Proc. Natl. Acad. Sci. USA 91, 9995-9999 (1994). 

In experiments, SAMe was found to prevent lipid peroxidation and to normalize the reduced glycogen content of hepatocytes in fiver damage. In further studies, its cytoprotective effect was also confirmed. (163, 166—171, 173, 177—181) This protective effect likewise applied to preneoplastic cell damage. The results concerning the prevention of cholestasis were impressive. In cirrhosis or severe fiver disease, there is a reduction in SAMe synthetase, glutathione, cysteine and phospholipid methyltransferase (together with a simultaneous deficiency in phosphatidylcholine formation, accompanied by disturbed membrane fluidity and decreased activity of Na /K -ATPase and Ca -ATPase). 

Progression of preneoplastic cells results in emergence of overt neoplasms, solid tumors (which require neoangiogenesis), or leukemia. 

Bursch, W., Lauer, B., Timmermann-Trosiener, 1., Barthel, G., Schuppler, J., and Schulte-Hermann, R. (1984). Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5, 453 58. 

Satoh, K., Kitahara, A., Soma, Y., Inaba, Y., Hatayama, I., and Sato, K., Purification and distribution of placental glutathione transferase A new marker enzyme for preneoplastic cells in the rat chemical hepatocarcinogenesis. Proc. Natl. Acad. Sci. U.SA. 82, 3964-3968 (1985). 

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