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Promotion of Hepatocarcinogenesis by Phenobarbital in c‐ myc /TGF‐α Transgenic Mice
Author(s) -
Sanders Sean,
Thorgeirsson Snorri S.
Publication year - 2000
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/1098-2744(200007)28:3<168::aid-mc5>3.0.co;2-e
Subject(s) - biology , carcinogenesis , tumor promotion , apoptosis , genetically modified mouse , phenobarbital , transgene , transforming growth factor , programmed cell death , tumor initiation , cancer research , transforming growth factor beta , endocrinology , medicine , cancer , gene , genetics
Previous work has shown that phenobarbital (PB) can promote cell survival in double transgenic c‐ myc /transforming growth factor (TGF)–α mice. This was achieved through a suppression of cell death brought about, at least in part, by a general increase in the level of bcl‐2 protein and a decrease in TGF‐β1 in treated versus untreated animals. No changes were found in TGF‐β type II receptor or in bcl‐X L protein levels. In the present work, we followed these animals for up to 31 wk of age (28 wk of treatment), by which time numerous tumors could be observed. A PB‐dependent decrease in tumor latency and a significant increase in multiplicity were seen. No statistically significant changes in the phenotype of foci, nodules, or neoplasms were observed after PB administration, and no effect on median tumor size was detected. Levels of the anti‐apoptotic protein bcl‐2 did not correlate with tumor formation in PB‐treated animals. However, in untreated mice, bcl‐2 was higher in tumors than in surrounding tissue in all tumors examined. We believe that the PB‐dependent modification of tumorigenesis in the livers of c‐ myc /TGF‐α mice was predominantly a result of the ability of this drug to block cell death during the early stages of tumor development. The effect of PB was exerted apparently by a pathway similar to, but separate from, that of TGF‐α. However, these pathways appear to converge downstream, having common effectors in the form of bcl‐2 family proteins. Mol. Carcinog. 28:168–173, 2000. © 2000 Wiley‐Liss, Inc.