Synthetic estrogens and tamoxifen as promoters of hepatocarcinogenesis.
Previously, we demonstrated that the synthetic estrogens mestranol and ethinyl estradiol (EE) were strong promoters of hepatocarcinogenesis initiated in intact female rats by prior treatment with diethylnitrosamine (J. D. Yager, H. A. Campbell, D. S. Longnecker, B. D. Roebuck, and M. C. Benoit, Cancer Res. 1984; 44:3862-3869). In subsequent studies designed to elucidate possible mechanisms of promotion by EE, we investigated whether the antiestrogen tamoxifen was antagonistic to the effects of EE (J. D. Yager, B. D. Roebuck, T. L. Paluszcyk, and V. A. Memoli, Carcinogenesis 1986; 7:2007-2014). In these and more recent studies we found that tamoxifen inhibited the stimulatory effects of EE on pituitary size, liver DNA synthesis, and, in cultured hepatocytes, the potentiation by EE of epidermal growth factor-induced DNA synthesis. Furthermore, tamoxifen also inhibited the ability of EE to promote hepatocarcinogenesis. However, paradoxically, tamoxifen alone enhanced the appearance of gamma-glutamyl transpeptidase positive foci in diethylnitrosamine-initiated livers indicating that it is a promoter of hepatocarcinogenesis.
Yager
J D
JD
Johns Hopkins School of Hygiene and Public Health, Division of Toxicological Sciences, Baltimore, Maryland 21205.
Shi
Y E
YE
D000818:Animals; D002273:Carcinogens; D004261:DNA Replication / Q000187:drug effects; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000009:adverse effects*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000737:chemistry / Q000188:drug therapy*; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013629:Tamoxifen / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005723:gamma-Glutamyltransferase / Q000737:chemistry / Q000187:drug effects
D002273:Carcinogens; D013629:Tamoxifen; D004052:Diethylnitrosamine; D004997:Ethinyl Estradiol; D004815:Epidermal Growth Factor; D005723:gamma-Glutamyltransferase