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.
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.
Van Ginckel
R
R
Janssen Research Foundation, Beerse, Belgium.
Janssens
B
B
Callens
M
M
Goeminne
N
N
Wouters
L
L
De Coster
R
R
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000284:Administration, Oral; D000735:Androstenedione / Q000097:blood; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D047072:Aromatase Inhibitors; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004958:Estradiol / Q000097:blood; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007986:Luteinizing Hormone / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D010052:Ovariectomy; D011374:Progesterone / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D047072:Aromatase Inhibitors; D002273:Carcinogens; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D014230:Triazoles; D013629:Tamoxifen; C060523:vorozole; D000735:Androstenedione; D011374:Progesterone; D004958:Estradiol; D015127:9,10-Dimethyl-1,2-benzanthracene; D007986:Luteinizing Hormone