Toremifene and tamoxifen produce identical effects in our endometrial cancer models. Therefore, it is possible that toremifene, like tamoxifen, may be associated with an increased incidence of endometrial cancer. In contrast, ICI 182,780 inhibited tamoxifen-stimulated endometrial cancer, both in the presence and in the absence of estrogen, suggesting that this drug may be safe with regard to the endometrium, even if it is used following tamoxifen, and that it may not result in an increased incidence of endometrial cancer. Indeed, it is even possible that ICI 182,780 may prove useful as an adjuvant agent in early stage endometrial cancer.

An HPLC/MS/MS method has been developed for the characterization and quantification of the cardiac glycosides oleandrin, odoroside, neritaloside and the aglycone oleandrigenin, all contained in a patented-hot-water extract of Nerium oleander L (Anvirzel). Qualitative analysis of such extracts was achieved using a hybrid tandem quadrupole time-of-flight (QqTOF) mass spectrometer. Collision-induced dissociation (CID) mass spectra of oleandrin, oleandrigenin, odoroside, and neritaloside were obtained with greater than 5 ppm mass accuracy and resolution routinely in excess of 8000 (fwhm). The detection limit for oleandrin of 20 pg (injected) was realized when the precursor-to-product ion transition, m/z 577 --> 373, was monitored. We have also applied the analytical method to the determination of oleandrin, oleandrigenin, neritaloside, and odoroside in human plasma following an intramuscular injection of Anvirzel.

No abstract

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.

Since tamoxifen is efficacious for the prevention of second primary breast neoplasms in humans and has a low reported incidence of acute side effects, several structurally related compounds have been developed for the treatment of breast cancer including toremifene and idoxifene. We have compared the karyotypic alterations that occur after a single per os administration of 35 mg/kg of tamoxifen, toremifene or idoxifene to female Sprague-Dawley rats. One day following treatment, the rats were sacrificed and the hepatocytes isolated and cultured. After 47 h in culture, colcemid was added for 3 h prior to harvest of the hepatocytes for karyotypic evaluation. At least 100 metaphase spreads were examined for each of five rats per treatment. Toremifene resulted in aneuploidy in 50 +/- 7% of the cells examined and idoxifene induced a 57 +/- 4% aneuploidy compared with the 85 +/- 7% level induced by tamoxifen. Since the level of aneuploidy in solvent-treated rats was 3 +/- 3 %, the induction of aneuploidy in at least 50% of the cells from rats treated with tamoxifen, toremifene or idoxifene was highly significant. Analysis of electron micrographs of cultures treated with these antiestrogens demonstrated a range of phenotypes including multipolar spindles in toremifene-treated rats and condensed chromosomes in the presence of an intact nuclear envelope in occasional idoxifene-treated rat hepatocytes. The exclusion of chromosomes from the spindle apparatus and the lagging of some chromosomes on the metaphase plate correlate with the high rate of induction of aneuploidy in the rat liver as determined by karyotypic analysis of hepatocytes from rats treated with these triphenylethylenes.