Chemopreventive effects of the aromatase inhibitor vorozole (R 83842) in the methylnitrosourea-induced mammary cancer model

The chemopreventive activity of the highly specific nonsteroidal aromataseinhibitor, vorozole, was examined in the methylnitrosourea (MNU)-inducedrat model of mammary carcinogenesis. Various doses of vorozole (0.08-1.25mg/kg body wt/day) were administered daily (by gavage) to femaleSprague-Dawley rats starting at 43 days of age. Seven days later, the ratswere given a single i.v. dose of MNU (50 mg/kg body wt). Rats werecontinually treated with vorozole until the end of the experiment (120 dayspost-MNU). Vorozole caused a dose dependent inhibition of mammary cancermultiplicity. The highest dose of vorozole (1.25 mg/kg body wt/day)decreased cancer multiplicity by approximately 90%, and simultaneouslydecreased cancer incidence from 100 to 44%. The next two highest doses ofvorozole (0.63 and 0.31 mg/kg body wt/day) inhibited MNU-induced mammarycancer multiplicity by 70-80%. Even the two lowest doses of vorozole (0.16and 0.08 mg/kg body wt/ day) decreased cancer multiplicity -50%. Serumlevel determinations were performed on a variety of endpoints at either 4or 24 h following the last dose of vorozole. Insulin-like growth factor(IGF)-1 levels were slightly, but significantly, increased by vorozoletreatment. Vorozole induced striking increases in serum testosterone levelsat 4 h at all the dose levels employed. Testosterone levels weresignificantly elevated over controls at 24 h in rats given the lower dosesof vorozole (0.08-0.31 mg/kg body wt/day), but were significantly lowerthan in rats administered the higher doses of vorozole (0.63 or 1.25 mg/kgbody wt/ day). This result presumably reflects the limited half- life ofvorozole in rats. In a second series of experiments, the effects of limitedduration of dosing with vorozole (2.5 mg/kg body wt/day) or intermittentdosing with vorozole were determined. Treatment of rats with vorozole forlimited time periods, from 3 days post-MNU administration until 30 or 60days post-MNU treatment, resulted in significant delays in the time toappearance of palpable cancers. However, these limited treatments did notgreatly affect the overall incidence or multiplicity of mammary cancerswhen compared with the MNU controls at the end of the study (150 dayspost-MNU). Finally, the effects of intermittent dosing with vorozole (2.5mg/kg body wt/day) were examined. Rats were administered cycles of vorozoledaily for a period of 3 weeks followed by treatment with the vorozolevehicle for the next 3 weeks (total of four cycles). Although thisintermittent treatment did inhibit the appearance of new tumors during eachof the periods that vorozole was administered, it did not cause regressionof palpable cancers.