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

Abstract

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 of 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 the 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.

Combination Endocrine Therapy in the Management of Breast Cancer

“…A dose-response relationship has been identified with vorozole plus tamoxifen in a rat model. A high dose of vorozole sufficient to produce similar estrogen suppression as seen with surgical castration combined with tamoxifen was less effective than either vorozole (high dose) or oophorectomy alone [5]. A marginally effective lower dose of vorozole was also combined with tamoxifen resulting in minor additional antitumor activity compared with vorozole alone, but to a lesser extent compared with oophorectomy [5].…”

Synergistic effects of bee venom, hesperidin, and piperine with tamoxifen on apoptotic and angiogenesis biomarker molecules against xerographic MCF-7 injected rats

“… Groups Dose/administration References Group I: (normal control group) (1ml 0.9%) saline orally plus injected with (0.5 ml) saline intraperitoneally Group II: (breast cancer control group) (1 × 10 7 MCF-7 cells/1 ml) around the teat of the mammary gland intradermally 16 Group III: (TMX group) (5mg/kg. body wt) once daily for 4 weeks orally 27 Group IV: (treatment groups) tumor bearing rats were treated with BV, Hes, and Pip for 4 weeks and divided into 3 sub-groups Sub-group IVA: (200 mg/kg body wt.) Hes once daily orally 28 Sub-group IVB: (50 mg/kg body wt.)…”

Patient Case Lessons: Endocrine Management of Advanced Breast Cancer

“…Early studies with fadrozole and vorozole did not consistently provide additional anti-tumor activity when used in combination with tamoxifen. 73,74 Later preclinical studies reported that letrozole alone was superior to tamoxifen, and added benefit was not evident with the combination treatment. The findings of studies conducted with anastrozole in combination with tamoxifen were similar to those with letrozole.…”