Activity of the antioestrogen trioxifene against N-nitrosomethylurea-induced rat mammary carcinomas

The therapeutic efficacy of a new antioestrogen, trioxifene, was compared with that of tamoxifen and ovariectomy against rat mammary tumours induced by N-nitrosomethylurea. In control animals, all but 1/59 tumours either progressed (52) or remained static (6) and 31 new tumours appeared. All 3 modes of therapy were highly effective. Trioxifene mesylate, (300 μg s.c. daily) induced regressions in 26/61 (42.6%) tumours, and stasis in 13 (21.3%). Nine new tumours appeared during trioxifene treatment. Tamoxifen (200 μg s.c. daily), produced regression of 22/50 tumours (44.0%), while 19 (38.0%) remained static and 2 new tumours developed. Ovariectomy caused regression of 35/56 (62.5%) tumours, growth was inhibited in another 8 (14.3%) and 2 new tumours developed. Regression after ovariectomy was greater compared with trioxifene therapy (P < 0.04), but no different for ovariectomy and tamoxifen, or tamoxifen and trioxifene. The relative binding affinity (RBA, OE₂ ≡ 100) of trioxifene (8.8-11) for NMU-induced mammary tumour oestrogen receptors was consistently 4-5× greater than that of tamoxifen. The comparative study in vitro did not parallel the finding in vivo. However, the RBA of monohydroxytamoxifen, a metabolite of tamoxifen, was the same or 2× greater than that of oestradiol, suggesting that tamoxifen's action may be facilitated by conversion to active metabolites. Further study of trioxifene's metabolites may increase our understanding of its mechanism of action in vivo.