EFFECTS OF COMBINED AND SEQUENTIAL TREATMENT WITH TAMOXIFEN AND THE AROMATASE INHIBITOR VOROZOLE ON 7,12-DIMETHYLBENZ(A) ANTHRACENE INDUCEDMAMMARY-CARCINOMA IN THE RAT

The aromatase inhibitor vorozole dose-dependently inhibited the growth of dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. An oral dose of 5 mg/kg per day brought about growth inhibition a nd reduction of tumor multiplicity similar to that produced by ovariec tomy. Tamoxifen (8 mg/kg per day) also reduced tumor growth, albeit to a lesser extent than did ovariectomy. Concomitant administration of v arying doses of tamoxifen with the fully effective dose of vorozole (5 mg/kg per day) tended to be less effective than ovariectomy or vorozo le alone. This is likely to be due to the estrogen-agonistic effects o f tamoxifen. Combination of tamoxifen with the partially effective dos e of vorozole (1 mg/kg per day) gave results comparable with those obt ained for either of these compounds used in monotherapy. Combining tam oxifen with a marginally active low dose of vorozole (0.2 mg/kg per da y) resulted in a minor additional growth inhibition as compared with t hat obtained with this dose of vorozole alone. Sequential treatment wi th tamoxifen (8 mg/kg per day) for 42 days and vorozole (5 mg/kg per d ay) for 42 days, and vice-versa, was performed with a drug-free interv al of 14 days between treatments. Tumors regressing under vorozole the rapy relapsed when subsequently treated with tamoxifen. In contrast, v orozole further reduced tumor volumes in rats previously treated with tamoxifen. Furthermore, monotherapy with tamoxifen as well as the two sequential tamoxifen-vorozole treatment schedules were in most cases l ess effective than vorozole monotherapy in inhibiting both tumor growt h and tumor multiplicity. Although extrapolation of these findings in cycling animals to the clinical situation, involving postmenopausal wo men, is not straightforward, these results warrant further studies in preclinical models. Moreover, clinical trials comparing the most effec tive aromatase inhibitors with tamoxifen in previously untreated postm enopausal patients with breast cancer may also be warranted.