Abstract
Abstract Background: ERr731® (trade names Phyto-Strol® or femi-loges®), an extract isolated from the roots of the Siberian rhubarb (Rheum rhaponticum), is used as an alternative treatment option for menopausal complaints. In addition, it is regularly used for the treatment of oligomenorrhoea or amenorrhea. The efficacy of the extract on treatment of menopausal complaints was shown in clinical trials and follow-up studies. Although clinical trials did not show changes of mammographic density, we addressed the question whether ERr731 is capable to stimulate experimental breast cancer in an estrogen dependent manner. Objective: The aim of the study was to assess whether or not the special extract ERr731® in a dosage relevant to human applications is capable to stimulate the growth of methyl-nitroso-urea (MNU) induced experimental breast cancer in ovariectomized Sprague-Dawley (SD) rats. Experimentals: 32 female SD rats were obtained at the age of postnatal day (PND) 40. On PND 49 and 56 all animals received an intra peritoneal MNU injection of 50 mg/kg body weight (BW). 28 days after the second injection 24 animals were ovariectomized (OvEx) and randomly allocated to 3 experimental groups, 8 animals were SHAM operated and served as positive control. SHAM operated animals (first positive control) and one group of OvEX animals (negative control) were fed a (phyto)estrogen-free diet. A second positive control group of OvEx animals received the phytoestrogen-free diet supplemented with 10 mg/kg diet of estradiol-benzoate. To mimic human exposure, ERr731®, in a dose of 0.067 mg/kg BW/d was chosen which is equivalent to 2.5 mg of the extract/kg chow. The experiment was terminated 25 weeks after MNU injection. Tumor-specific parameters, as well as uterine wet weights (UWW) were assessed. Results: Ovariectomy reduced the UWW > 6fold. Estradiol-benzoate restored UWW almost completely, whereas ERr731® did not lead to an increase in UWW. Tumor incidence in estrogenized animals was 62.5% (5/8 animals) in the SHAM group and 50% (4/8 animals) in the estradiol-benzoate treated group. No tumors were detected in OvEx negative controls and OvEx animals supplemented with the human relevant dose of ERr731®. The total numbers of tumors were 17 in the group of SHAM operated animals and 5 in the estradiol-benzoate treatment group. Conclusions: The human dose of ERr731® did neither exhibit estrogenic properties in the uterotrophic assay nor did it stimulate growth of MNU-induced breast cancers in OvEx SD rats, whereas estradiol supplementation at a low dose as well as estradiol levels in animals with a regular estrus cycle significantly promoted tumor growth. In this experimental model the used human dosage of ERr731® therefore appears safe regarding estrogen dependent growth stimulation of experimental MNU breast cancers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-05-09.
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