Effects of combined and sequential treatment with tamoxifen and the aromatase inhibitor vorozole on 7,12-dimethylbenz(a) anthracene-induced mammary carcinoma in the rat
Cancer Chemotherapy and Pharmacology(1996)
摘要
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 and reduction of tumor multiplicity
similar to that produced by ovariectomy. Tamoxifen (8 mg/kg per day) also reduced tumor growth, albeit to a lesser extent
than did ovariectomy. Concomitant administration of varying doses of tamoxifen with the fully effective dose of vorozole (5 mg/kg
per day) tended to be less effective than ovariectomy or vorozole alone. This is likely to be due to the estrogen-agonistic
effects of tamoxifen. Combination of tamoxifen with the partially effective dose of vorozole (1 mg/kg per day) gave results
comparable with those obtained for either of these compounds used in monotherapy. Combining tamoxifen with a marginally active
low dose of vorozole (0.2 mg/kg per day) resulted in a minor additional growth inhibition as compared with that obtained with
this dose of vorozole alone. Sequential treatment with tamoxifen (8 mg/kg per day) for 42 days and vorozole (5 mg/kg per day)
for 42 days, and vice-versa, was performed with a drug-free interval of 14 days between treatments. Tumors regressing under
vorozole therapy relapsed when subsequently treated with tamoxifen. In contrast, vorozole 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 less effective than vorozole monotherapy in inhibiting both tumor growth and tumor
multiplicity. Although extrapolation of these findings in cycling animals to the clinical situation, involving postmenopausal
women, is not straightforward, these results warrant further studies in preclinical models. Moreover, clinical trials comparing
the most effective aromatase inhibitors with tamoxifen in previously untreated postmenopausal patients with breast cancer
may also be warranted.
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关键词
Key words Rat,Aromatase,Vorozole,Tamoxifen,Breast cancer
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