Carcinogenesis, Vol 19, 1345-1351, Copyright © 1998 by Oxford University Press
RA Lubet, VE Steele, R DeCoster, C Bowden, M You, MM Juliana, I Eto, GJ Kelloff and CJ Grubbs
The chemopreventive activity of the highly specific nonsteroidal aromatase
inhibitor, vorozole, was examined in the methylnitrosourea (MNU)-induced
rat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25
mg/kg body wt/day) were administered daily (by gavage) to female
Sprague-Dawley rats starting at 43 days of age. Seven days later, the rats
were given a single i.v. dose of MNU (50 mg/kg body wt). Rats were
continually treated with vorozole until the end of the experiment (120 days
post-MNU). Vorozole caused a dose dependent inhibition of mammary cancer
multiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day)
decreased cancer multiplicity by approximately 90%, and simultaneously
decreased cancer incidence from 100 to 44%. The next two highest doses of
vorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammary
cancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16
and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serum
level determinations were performed on a variety of endpoints at either 4
or 24 h following the last dose of vorozole. Insulin-like growth factor
(IGF)-1 levels were slightly, but significantly, increased by vorozole
treatment. Vorozole induced striking increases in serum testosterone levels
at 4 h at all the dose levels employed. Testosterone levels were
significantly elevated over controls at 24 h in rats given the lower doses
of vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lower
than in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kg
body wt/ day). This result presumably reflects the limited half- life of
vorozole in rats. In a second series of experiments, the effects of limited
duration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittent
dosing with vorozole were determined. Treatment of rats with vorozole for
limited time periods, from 3 days post-MNU administration until 30 or 60
days post-MNU treatment, resulted in significant delays in the time to
appearance of palpable cancers. However, these limited treatments did not
greatly affect the overall incidence or multiplicity of mammary cancers
when compared with the MNU controls at the end of the study (150 days
post-MNU). Finally, the effects of intermittent dosing with vorozole (2.5
mg/kg body wt/day) were examined. Rats were administered cycles of vorozole
daily for a period of 3 weeks followed by treatment with the vorozole
vehicle for the next 3 weeks (total of four cycles). Although this
intermittent treatment did inhibit the appearance of new tumors during each
of the periods that vorozole was administered, it did not cause regression
of palpable cancers.
ARTICLES
Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model
NCI-DCP, Bethesda, MD 20892, USA. lubetr@dcpcepn.nci.nih.gov
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