Biomedical subjects

Michael W DeGregorio

Publications and source records attributed to Michael W DeGregorio.

4 recordsLinked to original sources

PubMed2005

Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a noninvasive premalignant lesion and is considered a precursor to invasive carcinoma. DCIS accounts for nearly 20% of newly diagnosed breast cancer, but the lack of experimentally amenable in vivo DCIS models hinders the development of treatment strategies. Here, we demonstrate the utility of a mouse transplantation model of DCIS for chemoprevention studies using selective estrogen receptor modulators (SERMs). This model consists of a set of serially transplanted lines of genetically engineered mouse mammary intraepithelial neoplasia (MIN) outgrowth (MIN-O) tissue that have stable characteristics. We studied the ovarian-hormone-responsiveness of one of the lines with a particular focus on the effects of two related SERMs, tamoxifen and ospemifene. METHODS: The estrogen receptor (ER) status and ovarian-hormone-dependence of the mouse MIN outgrowth tissue were determined by immunohistochemistry and ovarian ablation. The effects of tamoxifen and ospemifene on the growth and tumorigenesis of MIN outgrowth were assessed at 3 and 10 weeks after transplantation. The effects on ER status, cell proliferation, and apoptosis were studied with immunohistochemistry. RESULTS: The MIN-O was ER-positive and ovarian ablation resulted in reduced MIN-O growth and tumor development. Likewise, tamoxifen and ospemifene treatments decreased the MIN growth and tumor incidence in comparison with the control (P < 0.01). Both SERMs significantly decreased cell proliferation. Between the two SERM treatment groups, there were no statistically significant differences in MIN-O size, tumor latency, or proliferation rate. In contrast, the ospemifene treatment significantly increased ER levels while tamoxifen significantly decreased them. CONCLUSION: Tamoxifen and ospemifene inhibit the growth of premalignant mammary lesions and the progression to invasive carcinoma in a transplantable mouse model of DCIS. The inhibitory effects of these two SERMs are similar except for their effects on ER modulation. These differences in ER modulation may suggest different mechanisms of action between the two related SERMs and may portend different long-term outcomes. These data demonstrate the value of this model system for preclinical testing of antiestrogen or other therapies designed to prevent or delay the malignant transformation of premalignant mammary lesions in chemoprevention.

Animals↗

PubMed2005

Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women.

OBJECTIVE: To compare ospemifene and raloxifene regarding their effects on hormones, lipids, genital tract, and tolerability in postmenopausal women. DESIGN: A randomized, double-blind study in which 118 healthy postmenopausal women received 30 (n = 29), 60 (n = 30), or 90 mg (n = 30) of ospemifene or 60 mg (n = 29) of raloxifene for 3 months. RESULTS: There were no significant differences in the baseline characteristics between study groups. In comparison with raloxifene, follicle-stimulating hormone levels decreased significantly more in the 90-mg ospemifene group and sex hormone-binding globulin levels increased more in all ospemifene groups. Total cholesterol and low-density lipoprotein cholesterol levels decreased more in raloxifene than in ospemifene groups, although the difference in low-density lipoprotein cholesterol between 90-mg ospemifene and raloxifene was not significant. Endometrial thickness did not change in any study group and endometrial biopsies showed atrophy in the majority of subjects at 3 months. All ospemifene groups demonstrated a clear estrogenic effect on the vaginal epithelium, as seen in Pap smears. This was in sharp contrast to the raloxifene group, which had no effect on the vaginal epithelium. Kupperman index decreased in all study groups during treatment. The adverse events were mild, mainly single cases, and no clustering of events was observed. There were no clinically significant abnormal findings in laboratory safety parameters. CONCLUSIONS: Ospemifene, at the dose of 90 mg/day, was more estrogenic than raloxifene, as shown by changes in serum follicle-stimulating hormone and sex hormone-binding globulin levels. Neither agent stimulated endometrium, but in contrast to raloxifene, ospemifene had a clear estrogenic effect in the vagina. Further studies with ospemifene are needed in subjects with vaginal atrophy.

Double-Blind Method↗

PubMed2003

Pharmacokinetics of selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) are a class of compounds used to treat and prevent breast cancer and osteoporosis. SERMs currently approved for use in patients include tamoxifen, toremifene and raloxifene. These compounds are well tolerated in patients, and the most common adverse effects experienced in patients undergoing SERM therapy include vasomotor symptoms such as hot flashes and vaginal discharge. New SERMs currently under development for use in the treatment and prevention of osteoporosis and breast cancer include ospemifene, a derivative of toremifene, and arzoxifene, a compound very similar in structure to raloxifene. SERMs are administered orally at doses ranging from 20 to 60 mg/day. Tamoxifen and toremifene have a bioavailability of approximately 100%, whereas that of raloxifene is only 2%. SERMs are very highly bound to plasma proteins (>95%). Tamoxifen and toremifene are metabolised by the cytochrome p450 enzyme system, and raloxifene is metabolised by glucuronide conjugation. The terminal elimination half-lives of these drugs range from 27.7 hours to 7 days. The pharmacokinetics of these compounds are affected in hepatically impaired patients, but not in renally impaired patients. SERMs have several potential drug interactions with other agents, such as warfarin, rifampicin (rifampin), cholestyramine and aromatase inhibitors.

Age Factors↗

PubMed2002

SERMs: current status and future trends.

Selective estrogen receptor modulators, or SERMs, are a class of compounds that can act as estrogen receptor (ER) agonists in some tissues while acting as ER antagonists in others. SERMs are being evaluated and used to treat and prevent such diseases as breast cancer, osteoporosis, and cardiovascular disease. Currently, three primary SERMs are used clinically, which include tamoxifen, toremifene (triphenylethylenes), and raloxifene (a benzothiophene). Tamoxifen and toremifene have beneficial effects on bone and serum lipids, and are currently used to treat breast cancer. Both have stimulatory effects on the uterus. Raloxifene, indicated for the treatment and prevention of osteoporosis, also has beneficial effects on bone and serum lipids, but does not stimulate the uterus. All three are associated with venous thromboembolism and hot flashes. New SERMs to treat and prevent breast cancer, osteoporosis, and cardiovascular disease are undergoing clinical development, including idoxifene, droloxifene, ospemifene, lasofoxifene, arzoxifene, and MDL 103,323.

Animals↗