Modulation by indomethacin of diethylnitrosamine-induced early changes in c-myc and c-ras expression and late incidence of preneoplastic lesions in rat liver.
We measured the levels of c-myc and c-ras expression before and after diethylnitrosamine (DENA) treatment in the liver of rats previously submitted to partial hepatectomy (PH), in the presence or absence of indomethacin (IMC), given at a dose that reduced by 75% the incidence of preneoplastic foci of altered hepatocytes scored 8 weeks after application of the carcinogen. The time-course evolution of c-myc response to PH was similar in IMC-treated and untreated rats (with a peak at 3-8 h at least as high in IMC-treated animals as in the hepatectomized reference group), whereas the overall c-ras response was significantly reduced by the IMC treatment, resulting in much lower c-ras expression at 18-24 h posthepatectomy. Treatment with DENA 24 h after PH did not significantly modify c-ras expression compared to partially hepatectomized controls. In contrast, DENA treatment resulted in a marked transient increase in c-myc expression that was at least as pronounced, if not the same, in the IMC-treated animals. These results leave open the possibility that increased c-myc expression under DENA influence might play a role in foci induction but exclude that this might be sufficient. They are consistent with a role for c-ras expression in determining the susceptibility of hepatocytes towards the carcinogenic action of DENA.
Laboratory of Cytology and Experimental Cancerology, School of Medicine, Brussels, Belgium.
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Servais
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Taton
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Galand
D000818:Animals; D004052:Diethylnitrosamine; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D011905:Genes, ras; D007213:Indomethacin / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics / Q000517:prevention & control; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc; D011519:Proto-Oncogenes; D051381:Rats; D011919:Rats, Inbred Strains
D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D004052:Diethylnitrosamine; D007213:Indomethacin