Carcinogenesis, Vol. 20, No. 5, 843-850,
May 1999
© 1999 Oxford University Press
Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats
Centre International de Toxicologie, BP 563, Miserey, 27005 Evreux and
1 Besins Iscovesco, 5 rue du Bourg l'Abbé, 75003 Paris, France
Tamoxifen is widely used to treat oestrogen-dependent carcinoma of the breast. Previous long-term studies have shown that oral administration of tamoxifen induces hepatoproliferative lesions and hepatocellular tumours in rats. 4-hydroxytamoxifen is an active metabolite of tamoxifen undergoing clinical evaluation for the treatment of various non-malignant breast diseases by topical application. In the present study, 4-hydroxytamoxifen was administered daily by cutaneous application for 101 weeks to groups of 50 female Sprague–Dawley rats at 20, 140 or 1000 µg/kg/day. The product was applied with no occlusive bandage and oral ingestion was avoided by application of an Elizabethan collar for 6 h after administration. Treatment with 4-hydroxytamoxifen was clinically well tolerated and induced changes such as decreased food consumption and body weight gain, uterine and ovarian atrophy, mucification of vaginal epithelium and reduced mammary development, all of which were attributed to its pharmacological action. Mortality was significantly lower in the treated animals. The number of animals with palpable masses was similarly reduced. The incidence of mammary tumours and hypophyseal tumours was markedly lower in 4-hydroxytamoxifen-treated animals. The incidence of chronic tubulo-interstitial nephropathies, a common cause of mortality, was also lowered. There was no evidence of a carcinogenic action of 4-hydroxytamoxifen on the liver, genital organs or skin. Plasma levels of 4-hydroxytamoxifen were stable over the duration of the study and were proportional 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 hypophyseal tumours.
2 Present addresses: Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesdes, BP 14, 94403 Vitry sur Seine, France and
3 Biologie Servier, BP 255, Gidy, 45403 Fleury les Aubrais, France
4 To whom correspondence should be addressed Email: roy_forster{at}compuserve.com
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