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PubMed1999

Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis.

Idoxifene, a selective estrogen receptor modulator, was evaluated in male and female rats with adjuvant-induced arthritis (AA). AA was induced in Lewis rats with Mycobacterium butyricum in paraffin oil injected into the base of the tail, and the animals were treated with idoxifene prophylactically (days 0-21) or therapeutically (days 10-21). Efficacy was determined by measurements of paw inflammation, bone mineral content, and bone mineral density (BMD) with dual X-ray absorptiometry and by histological evaluation. Serum interleukin-6 levels were measured as a marker of the anti-inflammatory effects of the compound. Estrogen was included for comparison and was administered at 5 mg/kg, three times a week s.c. Prophylactic treatment of male AA rats with idoxifene at 10, 3, and 1 mg/kg and estrogen at 5 mg/kg significantly inhibited paw inflammation. There was improved joint integrity measured by BMD and reduced serum interleukin-6 levels in animals treated with 10 mg/kg/day idoxifene. Idoxifene and estrogen were as effective for AA in female Lewis rats as in male rats, significantly inhibiting paw inflammation and improving BMD. Histological evaluation of the tibiotarsal joints of female rats treated with 10 mg/kg showed protection of bone, cartilage, and soft tissue. Therapeutic treatment with either idoxifene or estrogen (starting on day 10 of disease) of male and female Lewis rats also was effective in reducing paw inflammation in these animals, although the effect was much less than that observed with the prophylactic dosing protocol.

Animals↗
PubMed2003

A review of selective estrogen receptor modulators and national surgical adjuvant breast and bowel project clinical trials.

Over the last 20 years tamoxifen, a selective estrogen receptor modulator, has been shown to be of clinical benefit to patients with advanced and resected hormone receptor-positive breast cancer. Tamoxifen has also been evaluated as a risk-reducing agent among patients at a high risk for the development of breast cancer and found to be effective, although it is associated with untoward adverse events (ie, stroke, venous thrombosis, and endometrial cancer). Recent analysis of National Surgical Adjuvant Breast and Bowel Project tamoxifen trials confirms that an increased risk for developing various endometrial malignancies exists across these protocols. Raloxifene, a selective estrogen receptor modulator available to treat osteoporosis, may also reduce the risk for developing breast cancer. The National Surgical Adjuvant Breast and Bowel Project is now comparing the risk-reducing activities of tamoxifen and raloxifene in women considered to be at a high risk for developing breast cancer. As newer potential risk-reducing agents are identified and placed into clinical prevention trials, patient selection, trial implementation methods, and accrual strategies must be developed to insure both that appropriate accrual targets are achieved and that women at clinically significant risk levels are accrued.

Antineoplastic Agents, Hormonal↗
PubMed2000

Selective estrogen receptor modulators: structure, function, and clinical use.

The sex hormone estrogen is important for many physiologic processes. Prolonged stimulation of breast ductal epithelium by estrogen, however, can contribute to the development and progression of breast cancer, and treatments designed to block estrogen's effects are important options in the clinic. Tamoxifen and other similar drugs are effective in breast cancer prevention and treatment by inhibiting the proliferative effects of estrogen that are mediated through the estrogen receptor (ER). However, these drugs also have many estrogenic effects depending on the tissue and gene, and they are more appropriately called selective estrogen receptor modulators (SERMs). SERMs bind ER, alter receptor conformation, and facilitate binding of coregulatory proteins that activate or repress transcriptional activation of estrogen target genes. Theoretically, SERMs could be synthesized that would exhibit nearly complete agonist activity on the one hand or pure antiestrogenic activity on the other. Depending on their functional activities, SERMs could then be developed for a variety of clinical uses, including prevention and treatment of osteoporosis, treatment and prevention of estrogen-regulated malignancies, and even for hormone replacement therapy. Tamoxifen is effective in patients with ER-positive metastatic breast cancer and in the adjuvant setting. The promising role for tamoxifen in ductal carcinoma-in-situ or for breast cancer prevention is evolving, and its use can be considered in certain patient groups. Other SERMs are in development, with the goal of reducing toxicity and/or improving efficacy, and future agents have the potential of providing a new paradigm for maintaining the health of women.

Animals↗
PubMed2002

Effects of the selective estrogen receptor modulator, raloxifene, on carotid artery pulsatility index in postmenopausal women.

OBJECTIVE: Estrogen replacement therapy after menopause reduces the incidence of arterial disease and cerebrovascular events. The reduced incidence also seems to be due to a positive effect of estrogens on brain blood flow as shown by a decrease in the carotid artery pulsatility index. Raloxifene, a second-generation selective estrogen receptor modulator, has aroused considerable interest because of its tissue-specific agonist-antagonist effect on estrogen receptors. However, there have been no studies on the effect of raloxifene on carotid blood flow after menopause. METHODS: A total of 66 healthy women in postmenopause for more than a year were divided randomly into 2 groups: the first group (n = 33; mean age +/- SD, 53.3 +/- 5.2 years) was treated with raloxifene (one 60-mg capsule per day) for 6 months, and the other group (n = 33; mean age +/- SD, 51.9 +/- 4 years) was untreated. Doppler ultrasonography was used to measure carotid artery pulsatility index (PI) at the beginning of the study and at 2-month intervals. RESULTS: A reduction in carotid artery PI was observed in all patients receiving raloxifene. No significant changes were observed in the control group. The reduction with respect to baseline values was 6.1%(P <.05) after 2 months, 11.2% (P <.05) after 4 months, and 13.2% (P <.05) after 6 months of therapy. The higher the baseline PI, the greater was its reduction after therapy. CONCLUSIONS: After 6 months of therapy, raloxifene induced a reduction in PI similar to that reported after estrogen therapy. The present results further our understanding of the mechanisms by which raloxifene might reduce the incidence of cardiovascular disease in postmenopausal women.

Carotid Arteries↗
PubMed2000

Distinct mechanisms of action of selective estrogen receptor modulators in breast and osteoblastic cells.

Raloxifene and idoxifene are selective estrogen receptor modulators (SERMs) that exhibit tissue-specific agonist or antagonist properties via interactions with the estrogen receptor (ER). Both compounds are similarly osteoprotective in the ovariectomized rat in vivo as assessed by measurement of bone mineral density, urinary pyridinium cross-links, and serum osteocalcin, suggesting a similar mechanism of action. However, we have identified a fundamental difference in this mechanism via the estrogen response element (ERE) in osteoblast-like cells. With the use of ERE-luciferase reporter constructs, raloxifene, like the complete ER-antagonist ICI-182780, acts as an antagonist via the ERE in osteoblastic cells. In contrast, idoxifene, like 17beta-estrogen itself and 4-OH-tamoxifen, acts as an agonist in osteoblastic cells via an ER/ERE-mediated mechanism. Both ICI-182780 and raloxifene inhibited the ERE-dependent agonist activity of 17beta-estradiol and idoxifene in osteoblastic cells. In contrast, in breast cells, raloxifene, idoxifene, 4-OH-tamoxifen, and ICI-182780 had no agonist activity and, indeed, raloxifene and idoxifene were potent antagonists of ERE-mediated 17beta-estradiol action, indicating an ERE-dependent mode of action in these cells. Although these SERMs exhibit a similar antagonist activity profile in breast cells, they can be distinguished mechanistically in osteoblastic cells.

Animals↗
PubMed2001

Effect of selective estrogen receptor modulators on reproductive tissues other than endometrium.

The objective of this paper is to review the published and unpublished knowledge of the effect of selective estrogen receptor modulators on reproductive tissues other than endometrium. Pharmaceutical companies developing or marketing selective estrogen receptor modulators (SERMs) were identified. The investigators at each company responsible for the conduct of investigational trials were contacted and queried about reports of adverse events in any ongoing or completed trials involving SERMs produced by their company. Levormeloxifene and idoxifene trials noted a higher proportion of surgery for pelvic organ prolapse in treated versus untreated women. The development of these pharmaceutical agents was discontinued, primarily for endometrial concerns. However, pelvic organ prolapse was reported to the FDA as an adverse event associated with both drugs. Study weaknesses preclude a definitive association between the agents and pelvic organ prolapse. The treated groups were not necessarily similar for confounding factors such as age, parity, obesity, cigarette smoking, and other risk factors for pelvic organ prolapse. Tamoxifen and raloxifene increase hot flash intensity and frequency. Ovarian cyst formation and uterine fibroid growth have also been reported with some SERMs. The identification and assessment of the impact of current and future SERMs on the pelvic floor and other genital tissues will be important to understanding their potential long-term application in disease treatment and prevention.

Breast Neoplasms↗
PubMed2002

Molecular perspectives on selective estrogen receptor modulators (SERMs): progress in understanding their tissue-specific agonist and antagonist actions.

Synthetic estrogen receptor ligands such as tamoxifen and raloxifene produce biologic responses which can be either estrogenic or anti-estrogenic, depending upon the tissue in which their action is examined. To reflect the fact that they are not 'pure' antagonists, such ligands have been more accurately termed selective estrogen receptor modulators (SERMs). Recent progress in our understanding of the molecular biology of estrogen receptor (ER) action has provided a great deal of evidence which promises to increase our understanding of the mechanism through which SERMs elicit their tissue-specific effects. The identification of numerous coactivators and corepressors which modulate receptor function and the realization of two subtypes of ER attest to the potential complexity through which SERMs produce diverse tissue-specific responses. Evidence from co-crystal structures of ER ligand-binding domains complexed with SERMs provides additional information as to how this class of ligands can elicit diverse biologic responses. SERMs also influence the stability of the ER protein, and recent information on the determinants of receptor stability and the role of proteasome-mediated protein degradation in ER-driven transcription also promises to give a fuller understanding of SERM biology. These aspects of the molecular biology of estrogen receptor action may help clarify the mechanism(s) of SERM biologic action and will be addressed in further detail in this review.

Animals↗
PubMed2002

Selective estrogen receptor modulators inhibit the effects of insulin-like growth factors in hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. RESULTS: Both primary and secondary HPT express estrogen receptors alpha and beta. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L (physiologic range) had no significant effects on IGF (I and II, P >.05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.

Adenoma↗
PubMedDate not supplied

Chemoprevention of breast cancer with selective estrogen receptor modulators: views from broadly diverse focus groups of women with elevated risk for breast cancer.

Selective estrogen receptor modulators (SERMs) are anti-estrogens that selectively antagonize the proliferative effects of estrogens on breast cells, thereby inhibiting or reversing neoplastic progression to clinical breast cancer. The goal is to administer these agents to healthy women with an elevated risk for breast cancer. The study reported here assessed the knowledge and attitude of 26 broadly selected women with an elevated risk for breast cancer who participated in three focus groups (eight to ten per group) that discussed the use of SERMs, such as tamoxifen and raloxifen. Data were analyzed by cross-case procedure using variable-oriented strategies. Acceptance of breast cancer chemoprevention treatment with SERMs was found to be influenced by various factors, including a knowledge of breast cancer risk factors, the perception of personal risk for breast cancer, and the perception of barriers and benefits to receiving chemoprevention treatment. The issues involved in making the decision to accept treatment with SERMs are discussed. Most of the participants in the groups indicated they were unlikely to accept breast cancer chemoprevention treatment with SERMs.

Adult↗
PubMed1998

[Selective estrogen receptor modulators as a new concept in preventing health risks of menopause].

Long-term estrogen deficiency after menopause is responsible for different disorders, which not only make the quality of life in the older age worse but also are the major causes of women's mortality. It is especially the case for cardiovascular disease, osteoporosis and dementia. The risk for these disorders can significantly be reduced by hormone replacement therapy (HRT). Unfortunately, the mean duration of the postmenopausal administration of HRT is too short to demonstrate its efficacy in preventing the mentioned diseases. In this review the new therapeutic possibilities are discussed, called selective estrogen receptor modulators (SERMs). These structurally heterogeneous compounds interact with estrogen receptors and act as either estrogen-agonists or--antagonists according to the type of organ and physiological context (i.e., dose, target tissue and hormone concentration in the tissue). The evaluation of the effects of these compounds led to the better understanding of both antiestrogens and the whole steroid signaling system. The research of the clinical properties of SERM showed their potential benefit in the long-term care of the women in their non-reproductive period of life and demonstrated the possibility to overcome some drawbacks of HRT.

Cardiovascular Diseases↗
PubMed2000

Effects of raloxifene, a selective estrogen receptor modulator, on thymus, T cell reactivity, and inflammation in mice.

Raloxifene is a selective estrogen receptor modulator approved for prevention of osteoporosis in postmenopausal women. It is selective by virtue of having estrogen agonistic effects in bone, vessels, and blood lipids, while it is antagonistic with mammary and uterine tissue. The aim of the study was to examine whether the raloxifene analogue LY117018 (LY) has estrogenic effects on the thymus, T cell responsiveness, and inflammation. Oophorectomized normal mice were treated with subcutaneous injections of equipotent antiosteoporotic doses of LY (3 mg/kg) and 17beta-estradiol (E2) (0.1 mg/kg) or vehicle as controls. Effects on thymus were studied by analyses of thymus weight, cellularity, and CD4 and CD8 phenotype expression and histology, while inflammation was determined as T-cell-mediated delayed-type hypersensitivity (DTH) and granulocyte-mediated footpad swelling. LY lacked the suppressive properties of E2 on DTH and granulocyte-mediated inflammation. Furthermore, LY induced only minor thymus atrophy compared with E2 and did not, in contrast to E2, alter the thymic CD4/CD8 phenotypes. These results clearly demonstrate that raloxifene principally lacks the modulatory effects of estrogen on T cell responsiveness and inflammation. Our data are discussed in the context of recent findings in estrogen receptor biology and also with respect to estrogen-mediated alteration of autoimmune rheumatic diseases.

Animals↗
PubMedDate not supplied

Suppression of elevated cartilage turnover in postmenopausal women and in ovariectomized rats by estrogen and a selective estrogen-receptor modulator (SERM).

OBJECTIVE: Several observational studies indicate that estrogen deficiency increases the incidence of osteoarthritis in postmenopausal women. To validate this observation, we investigated the effects of ovariectomy (OVX) on cartilage erosion in rats using histology and an established bio-assay of cartilage-specific collagen type II degradation products (CTX-II). Furthermore, we investigated whether estrogen and levormeloxifene, a selective estrogen-receptor modulator (SERM), can prevent the OVX-induced changes in cartilage degradation. The clinical relevance was assessed in postmenopausal women by measuring the changes in CTX-II during 12-month treatment with levormeloxifene versus placebo. DESIGN: Sixty 6-month-old rats were divided in five groups. One group was subjected to sham and the others to OVX, followed by treatment with vehicle alone, estradiol or 0.2 mg/kg/day or 5 mg/kg/day of levormeloxifene. The rats were treated for 9 weeks with biweekly blood and urine sampling for measurement of bone resorption and cartilage turnover. After study termination, hind knees were removed for histological analysis of erosions. The effect of levormeloxifene in post-menopausal women was assessed by measuring CTX-II in samples from 301 women who were participating in a phase II study of this SERM. RESULTS: OVX rats showed significant increases in the urinary excretion of CTX-II. After 9 weeks this was manifested as increased surface erosion of knee articular cartilage compared with sham-operated rats. Treatment with estrogen or levormeloxifene prevented the OVX-induced changes. There was a significant correlation between the 4-week changes in CTX-II and cartilage erosion at week 9 (r = 0.64, P < 0.001). In postmenopausal women treated with levormeloxifene, the urinary excretion of CTX-II was decreased by approximately 50% and restored CTX-II levels to the premenopausal range. CONCLUSIONS: This study is the first to demonstrate that a SERM suppresses cartilage degradation in both rodents and humans, suggesting potential therapeutical benefits in the prevention of destructive joint diseases such as osteoarthritis.

Aged↗
PubMed2001

Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors.

Glutamate and glutamate receptors are well known to play a major excitatory role in the brain. Recent findings on ovarian steroids and selective estrogen receptor modulators (SERMs) activity on rat brain AMPA and NMDA receptors are reviewed. Ovarian steroid withdrawal by ovariectomy is without effect on NMDA and AMPA receptors in most brain regions, except in hippocampus, where it decreases NMDA receptor specific binding, compared to intact rat values. Estradiol treatment increases hippocampal NMDA receptor specific binding of ovariectomized rats while it decreases this binding in frontal cortex and striatum. Estradiol treatment has no effect on AMPA receptor specific binding in hippocampus, but decreases binding in frontal cortex, striatum and nucleus accumbens. Progesterone and estradiol+progesterone treatments decrease NMDA, but not AMPA receptors specific binding in frontal cortex compared to ovariectomized rats. No effect was observed in other brain regions. Tamoxifen and raloxifene are SERMs with varying effects on estrogen responses in mammary, bone and uterine tissues. Tamoxifen and raloxifene have estrogenic activity upon modulation of brain NMDA and AMPA receptors. Using specific ligands for binding autoradiography of NMDA receptor subunits and specific probes for subunits measured by in situ hybridization, it was shown that estradiol and SERMs modulate NR1 and NR2B subunits whereas the NR1/2A subunit remains unchanged. In summary, regional agonist estrogenic activity on brain AMPA and NMDA receptors of tamoxifen and raloxifene, like that of estradiol, is observed, whereas progesterone has limited effects or opposes the estradiol effect.

Animals↗
PubMed2006

Novel chromene-derived selective estrogen receptor modulators useful for alleviating hot flushes and vaginal dryness.

A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.

Animals↗
PubMedDate not supplied

Plant 2-arylobenzofurans demonstrate a selective estrogen receptor modulator profile.

We have isolated from the plant Onobrychis ebenoides three novel arylobenzofurans with binding affinity for the estrogen receptor. In this study, we evaluated these arylobenzofurans, namely ebenfuran I, ebenfuran II and ebenfuran III for their potential selective estrogen receptor modulator (SERM)-like properties. We examined their ability, (1) to induce the insulin growth factor binding protein-3 (IGFBP-3) in MCF-7 breast cancer cells, (2) to stimulate differentiation and mineralization of osteoblastic cell culture by histochemical staining for alkaline phosphatase, Alizarin Red-S staining and calcium levels in the supernatants and (3) to inhibit cell proliferation of cervical adenocarcinoma (Hela) cells by use of the MTT assay. An estrogen receptor mediated effect was investigated by carrying out chloramphenicol acetyl transferase (CAT) assay on transient MCF-7 transfectants. Estradiol and the "pure" antiestrogen ICI 182780 were included to serve as control samples of the estrogenic and antiestrogenic effect respectively. Our data reveal that ebenfuran II is a highly potent SERM, exhibiting antiestrogenic activity in breast cancer cells via the estrogen receptor, estrogenic effect on osteoblasts and no stimulatory effect on cervix adenocarcinoma cells. In conclusion, our study is the first to demonstrate that plant derived arylobenzofurans show a SERM profile and may be considered for the prevention and treatment of diseases such as breast cancer, cervical cancer and osteoporosis.

Adenocarcinoma↗
PubMed1998

Selective estrogen receptor modulators: an alternative to hormone replacement therapy.

Estrogen is a key regulatory hormone, which in addition to its role in reproduction, affects a number of physiological systems, including the skeleton and cardiovascular system. The important role of estrogen in various tissues is perhaps most evident in postmenopausal women who, in addition to menopausal symptoms, experience increases in osteoporosis and coronary heart disease as their estrogen levels decline. Estrogen replacement, while effective against osteoporosis and heart disease, produces a number of side effects associated with the breast and uterus which limits compliance. Selective estrogen receptor modulators (SERMs), such as raloxifene and tamoxifen, produce beneficial estrogen-like effects on bone and lipid metabolism, while antagonizing estrogen in reproductive tissue. SERMs can be distinguished from each other in reproductive tissue, particularly the uterus, by their activity profile. For example, while triphenylethylenes like tamoxifen behave as partial agonists, raloxifene (a benzothiophene) behaves as a complete antagonist in the uterus. The SERM profile is distinct from that of full estrogens (ie. 17beta-estradiol or 17alpha-dihydroequilenin) which behave as estrogen agonists in all tissues and pure estrogen antagonists (i.e. ICI-164,384) which exhibit only an estrogen antagonist profile in a battery of tissue types. The precise mechanism by which SERMs produce this tissue-selective pharmacology remains a question. It is clear, however, that for raloxifene, both the estrogen agonist effects on bone and cholesterol metabolism as well as the estrogen antagonist effects in uterine and mammary tissue involve high affinity interaction with the estrogen receptor. The estrogen antagonist activity is mediated via classical pharmacological competition for estrogen receptor binding. The estrogen agonist activity, in bone for example, appears to involve novel post-receptor pathways and non-classical estrogen response element(s) which are activated by SERMs. These novel response elements may represent natural pathways which respond to estrogen metabolites in vivo.

Bone Resorption↗
PubMed2001

Effects of the new selective estrogen receptor modulator LY353381.HCl (Arzoxifene) on human endometrial cancer growth in athymic mice.

PURPOSE: Arzoxifene (Arzox) is a novel benzothiophene analogue with selective estrogen receptor modulator activity similar to raloxifene. Arzox is being developed as a treatment for breast cancer and has a predominantly antiestrogenic effect on the rodent uterus. Our objectives were to verify whether the novel selective estrogen receptor modulator, Arzox, can be a good first-line agent and also be effective at controlling the growth of endometrial cancer after exposure to tamoxifen (Tam). EXPERIMENTAL DESIGN: We compared the effects of Tam and Arzox on the growth of estrogen responsive ECC-1 endometrial cancer cells in vitro, and we determined their antitumor effects on ECC-1 and EnCa101 endometrial carcinoma growth in athymic mice. RESULTS: We observed that estrogen receptor protein expression is down-regulated by Arzox to the same extent as raloxifene, whereas 4-hydroxytamoxifen, the active metabolite of Tam, does not affect estrogen receptor protein levels. Tam and Arzox inhibit the growth of Tam-naïve ECC-1 tumors in athymic mice. However when Tam-stimulated or estrogen-stimulated (which had been treated with Tam previously) EnCa101 endometrial tumors were treated with Tam or Arzox, we observed a stimulatory effect of both compounds in these models. CONCLUSIONS: The results indicate that Arzox may be a good first-line agent, but it may be ineffective at controlling the growth of endometrial cancer after exposure to Tam. Our data suggest that Arzox stimulates endometrial tumor growth to at least the same extent as Tam, thereby suggesting a limited role as a second-line agent for the patient on Tam who develops occult endometrial cancer.

Animals↗
PubMed2005

Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4'-fluoro substitution prevents quinoid formation.

Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4'-F-DMA, was synthesized. 4'-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4'-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4'-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4'-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.

Alkaline Phosphatase↗