Tamoxifen induces hepatic aneuploidy and mitotic spindle disruption after a single in vivo administration to female Sprague-Dawley rats.
Tamoxifen has found extensive use in the treatment of all stages of human breast cancer. The efficacy of tamoxifen treatment for the prevention of second primary tumors and its chemosuppressive action in animal models have led to initiation of clinical trials to test its efficacy for prevention of this disease in women. Recently, tamoxifen has been shown to induce hepatocellular carcinomas in rats. For determination of the mechanism of induction of these tumors and assessment of the possibility of risk of human cancer development from tamoxifen treatment, female Sprague-Dawley rats (five rats per treatment) were administered tamoxifen at doses ranging from 0.3 to 35 mg/kg. One day after treatment, the rats were sacrificed, and the hepatocytes were isolated and cultured for 50 h. Colcemid was added 3 h prior to harvest, and the hepatocytes were then prepared for karyotypic evaluation. One hundred metaphase spreads were examined per animal. Tamoxifen treatment resulted in the induction of aneuploidy in approximately 70% of the examined hepatocytes at the doses used. In addition, premature condensation (2-10%) and endoreduplication (5-10%) were observed in hepatocytes of rats treated with tamoxifen. Furthermore, exchanges between chromosomes as well as chromosome breakage were observed. Examination of the cultured hepatocytes from rats treated with tamoxifen by electron microscopy demonstrated both unipolar spindles and incompletely elongated spindles. Exposure of rats to a single in vivo dose of tamoxifen produced multiple changes in rat hepatocytes including clastogenic damage at doses comparable to that administered to humans. The occurrence of aneuploidy induction, premature condensation, chromosome breakage, and improper mitotic spindle formation indicates that risk versus benefit of tamoxifen treatment should be carefully evaluated.
Sargent
L M
LM
McArdle Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison 53706.
Dragan
Y P
YP
Bahnub
N
N
Wiley
J E
JE
Sattler
C A
CA
Schroeder
P
P
Sattler
G L
GL
Jordan
V C
VC
Pitot
H C
HC
D000782:Aneuploidy; D000818:Animals; D002869:Chromosome Aberrations / Q000139:chemically induced*; D025063:Chromosome Disorders; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects*; D011725:Pyridines / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D008941:Spindle Apparatus / Q000187:drug effects*; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects*
D011725:Pyridines; D013629:Tamoxifen; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene