Tamoxifen induces hepatocellular carcinoma in rat liver: A 1-year study with two antiestrogens

Abstract

The effects of equimolar doses of the triphenylethylene antiestrogens tamoxifen and toremifene on female Sprague-Dawley rat liver were studied in a 52-week toxicity study which included a 13-week recovery period. Liver tumors were found in four out of five rats at the highest dose level of tamoxifen (45 mg/kg per day) after 52 weeks of dosing, and these appeared to be hepatocellular carcinomas in three rats. After the 13-week recovery period all surviving rats in the highest tamoxifen dose group had large liver tumors (diameter up to 2 cm) which appeared to be hepatocellular carcinomas in five out of six rats. No tumor was observed in the toremifene-treated rats (48 mg/kg per day) either after 52 weeks of dosing or after the recovery period. Electron microscopic morphometric analysis after 52 weeks of dosing revealed that at the tamoxifen high dose level, the volume densities of the peroxisomes, mitochondria, and residual bodies were elevated in the nonneoplastic hepatocytes of the rats. In the neoplastic hepatocytes of the tamoxifen-treated rats the volume density of nuclei was slightly elevated. The slight proliferation of peroxisomes and mitochondria might be related to tumor development in the tamoxifen treated rats.

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

“…initiation of tumours or mutagenesis of p53 tumour suppressor gene (Styles et al, 1994;Vancutsem et al, 1994). As TAM induces DNA adducts and is carcinogenic in the rat liver (Han and Liehr, 1992;Hard et al, 1993;Hirsimaki et al, 1993;Montandon et al, 1994), non-hormonal mechanisms might be preferentially related to the initiation of secondary malignancies. The recent report that TAM-treated patients have an increased incidence of gastrointestinal tumours is disconcerting (Rutqvist et al, 1995).…”

“…The most common adverse drug reaction consists in climacteric-like symptoms, but the drug has also been reported to generate DNA adducts in human hepatocyte cultures and in rats and Syrian hamsters (Han et al, 1992;White et al, 1992;Hard et al, 1993). TAM is a liver carcinogen in rats (Hirsimaki et al, 1993;Vancutsem et al, 1994) and it increases the risk of endometrial and gastrointestinal cancers in patients (Fisher et al, 1994; De Gregorio et al, 1995;Rutqvist et al, 1995) and increases the number of polyps in the endometrium (Lahti et al, 1993). Clearly, an anti-oestrogen that lacks these carcinogenic characteristics while retaining the beneficial effects of TAM is desirable (Zito, 1994).…”

Toremifene in the treatment of breast cancer

“…The finding that tamoxifen at high doses caused liver tumors in rats [61] raised concern that it may be mutagenic in humans. The mechanism of this effect in laboratory animals was believed to be due to DNA adduct formation by metabolites of tamoxifen, although this has more recently been questioned [62] .…”

Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention

“…Tamoxifen decreases the incidence of mammary tumors in rodent carcinogenesis studies [Gottardis et al, 1996]. There has been concern that preclinical studies have demonstrated an increased risk of liver tumors in rodent models [Hirsimaki et al, 1993;Williams et al, 1993]; however, there has been no increase in liver cancer in humans [Muhlemann et al, 1994;Wilking et al, 1997]. Adjuvant studies of tamoxifen demonstrate a 30 -50% decrease in the development of contralateral breast cancer in tamoxifen-treated women [EBCTCG, 1998] and tamoxifen is well tolerated with potential beneficial effects on postmenopausal bone mineral density and lipid profiles [Love et al, 1991[Love et al, , 1992[Love et al, , 1994.…”