Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital.
Tamoxifen administered in the diet (420 ppm) to Wistar rats (TOX:P) for only 3 months caused cumulative hepatic DNA damage as assessed by 32P-postlabeling, consistent with the proposal that tamoxifen is a genotoxic carcinogen in this species. Promotion of tumor development with phenobarbital after discontinuation of dietary tamoxifen resulted in the formation of liver carcinomas after 9 months. At 12 and 20 months in this study, the majority of these rats had liver carcinomas. Rats treated with tamoxifen for 3 months but not promoted with phenobarbital also developed liver tumors over a longer period of time. These tumors were predominantly adenomas, with one carcinoma, and occurred at a lower incidence than the tumors produced by promotion with phenobarbital. Rats treated with phenobarbital alone did not develop tumors after 20 months. Tamoxifen-induced DNA adducts were relatively persistent, with only a 38% decrease 3 months after tamoxifen treatment had been discontinued. This demonstrates that, in a susceptible species (the rat), tamoxifen can cause initiation of liver cancer after only 3 months exposure. It is proposed that the persistence of such DNA adducts may account for the ability of phenobarbital to promote a high incidence of liver carcinoma, even after discontinuation of tamoxifen treatment. These data are relevant to the concern for women given prophylactic tamoxifen for long periods in that even if there is a relatively small amount of cumulative tamoxifen-induced liver DNA damage, liver tumors could be promoted by other agents, even after the cessation of tamoxifen treatment.
Carthew
P
P
MRC Toxicology Unit, Hodgkin Building, University of Leicester, United Kingdom.
Martin
E A
EA
White
I N
IN
De Matteis
F
F
Edwards
R E
RE
Dorman
B M
BM
Heydon
R T
RT
Smith
L L
LL
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D004032:Diet; D004357:Drug Synergism; D005260:Female; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D010634:Phenobarbital / Q000633:toxicity*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013629:Tamoxifen / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors
D014408:Biomarkers, Tumor; D002273:Carcinogens; D018809:Proliferating Cell Nuclear Antigen; D013629:Tamoxifen; D010634:Phenobarbital