Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats

Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the brea st. Previous long-term studies have shown that oral administration of tamox ifen induces hepatoproliferative lesions and hepatocellular tumours in rats , 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinic al evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administ ered daily by cutaneous application for 101 weeks to groups of 50 female Sp rague-Dawley rats at 20, 140 or 1000 mu g/kg/day. The product was applied w ith no occlusive bandage and oral ingestion was avoided by application of a n Elizabethan collar for 6 h after administration. Treatment with 4-hydroxy tamoxifen was clinically well tolerated and induced changes such as decreas ed food consumption and body weight gain, uterine and ovarian atrophy, muci fication of vaginal epithelium and reduced mammary development, all of whic h were attributed to its pharmacological action. Mortality was significantl y lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tum ours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidenc e of chronic tubulo-interstitial nephropathies, a common cause of mortality , was also lowered. There was no evidence of a carcinogenic action of 4-hyd roxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydr oxytamoxifen were stable over the duration of the study and were proportion al to the administered dose, exceeding clinical plasma levels by 60-fold at the high dose-level. In conclusion, 4-hydroxytamoxifen is not carcinogenic in the rat and reduces the incidence of spontaneous mammary and hypophysea l tumours.