Carcinogenesis, Vol 18, 2247-2253, Copyright © 1997 by Oxford University Press
GM Williams, MJ Iatropoulos and S Karlsson
A striking difference between two structurally related anti-estrogen
medicines is that tamoxifen is strongly hepatocarcinogenic in the rat,
whereas toremifene lacks such activity. To study the basis for this
difference, the initiating potential of tamoxifen and toremifene were
studied by measurement of rapid induction of hepatocellular altered foci
(HAF) that express placental-type glutathione S-transferase in the livers
of female Sprague-Dawley (S-D) rats and female Fischer 344 (F344) rats.
Both agents were administered by gavage at equimolar doses up to a dose
that produced marked weight gain suppression. In rats given the high dose
of 40 mg/kg per day tamoxifen continuously for 36 weeks, 75% of S-D rats
developed liver neoplasms, in contrast to only 10% of F344 rats. In the S-D
strain, tamoxifen produced a tendency to increased HAF at 2 weeks at the
dose of 40 mg/kg per day and by 12 weeks, a dose-related increase was
evident. In contrast, toremifene induced no HAF even at the equimolar high
dose of 42.4 mg/kg per day for 12 weeks. The induction of HAF by tamoxifen
was less in the F344 rats. Neither agent elicited increases in
hepatocellular proliferation in S-D or F344 rats. When phenobarbital was
administered for 24 weeks as a promoting agent after the anti-estrogens,
S-D rats given tamoxifen at 20 mg/kg per day for 12 weeks, developed liver
neoplasms, but not F344 rats or rats of either strain given even a higher
dose (42.4 mg/kg) of toremifene. Thus, tamoxifen has initiating activity in
these rat strains whereas toremifene does not.
ARTICLES
Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat liver
American Health Foundation, Valhalla, New York, USA.
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