idoxifene and Adenocarcinoma

Our purpose was to evaluate the use of transvaginal ultrasonography for the detection of endometrial disease in a population of postmenopausal women who were without symptoms.. Postmenopausal women were screened for potential inclusion in 2 multicenter, double-blind, placebo-controlled studies of 2 years' duration to evaluate the safety and efficacy of idoxifene in the prevention of osteoporosis. Baseline endometrial evaluation was performed by transvaginal ultrasonography and aspiration biopsy of the endometrium.. A total of 1926 women were screened by transvaginal ultrasonography, and 1833 of them had endometrial thickness < or =6 mm. Five cases of endometrial abnormality (adenocarcinoma [n = 1] and atypical hyperplasia [n = 4]) were detected in the 1750 women from this cohort who underwent biopsy. The negative predictive value was >99%. One case of adenocarcinoma was detected in the 42 women who had endometrial thickness >6 mm and underwent biopsy. However, the sampling rate (45%) of women with endometrial thickness >6 mm was too low for confidence in the positive predictive value of 2%.. Despite a high negative predictive value, transvaginal ultrasonography may not be an effective screening procedure for detection of endometrial abnormality in untreated postmenopausal women who are without symptoms.

Topics: Adenocarcinoma; Biopsy, Needle; Double-Blind Method; Endometrial Hyperplasia; Endometrial Neoplasms; Endometrium; Female; Humans; Osteoporosis, Postmenopausal; Placebos; Postmenopause; Sensitivity and Specificity; Tamoxifen; Ultrasonography; Uterine Diseases

Idoxifene is a novel selective estrogen (E2) receptor (ER) modulator that is currently in clinical development for the treatment of breast cancer. Compared to tamoxifen, idoxifene is metabolically more stable, with a higher relative binding affinity for the ER and reduced agonist activity on breast and uterine cells. Idoxifene also inhibits calmodulin, a calcium-binding protein that is involved in cell signal transduction pathways. In this study, the abilities of idoxifene and tamoxifen to antagonize E2-dependent MCF-7 xenograft growth in oophorectomized athymic mice were compared. The basis for idoxifene's antitumor activity was examined by comparing the effectiveness of the clinically used transisomer (referred to here as idoxifene) with its cis-isomer, which has a 50-fold lower relative binding affinity for ER than idoxifene but similar calmodulin-inhibitory activity. Changes in tumor cell proliferation, apoptosis, and ER-dependent protein expression were studied. Both idoxifene and tamoxifen significantly inhibited E2-dependent tumor growth, whereas cis-idoxifene had little effect. Withdrawal of E2 support induced significant tumor regression due to impaired cell proliferation (Ki-67 score, 9 versus 51% compared to E2 controls) and induction of apoptosis (3.6 versus 0.9% compared to E2 controls). Both anti-E2s inhibited cell proliferation and caused a significant 3-fold induction of apoptosis in E2 supported tumors after 1 week, which was maintained for 3 months with idoxifene (3.1 versus 0.48% compared to E2 controls) but decreased back to baseline in tumors treated with tamoxifen (0.69%). In contrast, cis-idoxifene had no effect on either cell proliferation or apoptosis. Both tamoxifen and idoxifene initially induced ER expression, whereas prolonged therapy with tamoxifen significantly reduced progesterone receptor levels. In conclusion, idoxifene resulted in similar inhibition of E2-dependent MCF-7 xenograft growth compared with tamoxifen, an effect that is mediated via ER rather than through calmodulin. Sustained induction of apoptosis may contribute to prolonged antagonism of E2-dependent growth, and it occurred to a greater extent following 3 months of idoxifene, compared to tamoxifen.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Hormonal; Apoptosis; Breast Neoplasms; Drug Screening Assays, Antitumor; Estradiol; Estrogen Antagonists; Female; Humans; Ki-67 Antigen; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Ovariectomy; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen