Ravindra B. Saudagar1*, Nachiket S. Dighe2, Deepak S. Musmade3 , Vinayak M. Gaware4 and D. A. Jain5
1Department of Pharmaceutical Chemistry, R.G.Sapkal College of Pharmacy, Nashik, M.S. India.
2Department of Pharmaceutical Chemistry, Pravara Rural College of Pharmacy, Loni, MS, India-413736.
3Department of Pharmaceutical Chemistry, Sanjivani College of Pharmaceutical Education and Research, Kopargaon, MS. India.
4Department of Pharmaceutical Chemistry, College of Pharmacy, Chincholi, MS, India.
5Department of Pharmaceutical Sciences and Research, Bhagwant University, Ajmer, Rajasthan, India
*Corresponding Author E-mail: email@example.com
Selective estrogen receptor modulators are the class of a chemical compounds acting on a estrogen receptors. These are selectively inhibit or stimulate the estrogen like actions in various tissues. SERMs play a key role in breast cancer chemoprevention. These agents antagonize estrogens in some tissues and mimic their action in others. The mechanism for tissue selectivity appears to be related to differences in their molecular and three-dimensional structures, which affect the transcriptional activity of the activated estrogen receptor. For example, tamoxifen and toremifene act as estrogen antagonists in breast tissue and as estrogen agonists in the endometrium. The present review article is directed towards highlighting the importance of SERMs in treatment of breast cancer.
Selective Estrogen Receptor Modulators (SERMs) are a class of compounds that act on the estrogen receptor.1 A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively inhibit or stimulate estrogen-like action in various tissues. Phytoserms are scientifically accepted SERMs from a botanical source. The rationale behind cancer chemoprevention is based on the hypothesis that the multi-step process of carcinogenesis can be modulated, arrested or reversed by natural or synthetic agents2. Chemoprevention can be divided into primary (to prevent the onset of disease in healthy individuals at risk); secondary (to treat a population with a premalignant condition in order to arrest the development of cancer) or tertiary (to protect subjects cured of an initial cancer against second primary tumours).
SERMs play a key role in breast cancer chemoprevention. These agents antagonise estrogens in some tissues and mimic their action in others. The mechanism for tissue selectivity appears to be related to differences in their molecular and three-dimensional structures, which affect the transcriptional activity of the activated estrogen receptor. For example, tamoxifen and toremifene act as estrogen antagonists in breast tissue and as estrogen agonists in the endometrium. Conversely, raloxifene behaves as an estrogen antagonist in both the breast and the endometrium3.
The SERMs belong to several different chemical classes such as triphenylethylenes, benzothiophenes, naphtalenes, indoles, chromane and benzopyran compounds, all of which are not steroidal compounds. By contrast, most of the ‘pure’ antioestrogens are derivatives of the natural oestrogen, oestradiol, although recently ‘pure’ antiestrogens with a non-steroidal chemical structure have been developed.
The pharmacokinetics of the SERMs is complex and the knowledge is incomplete. This may be due to a combination of physicochemical properties of the compounds and low blood concentrations of the drugs and their metabolites (usually in the range of 1–200 ng/ml), resulting in analytical difficulties. In addition, for several of the compounds, a long half life makes protocols for determination of these parameters difficult 6.
ABSORPTION AND BIOAVAILABILITY7, 8
In general the absorption of SERMs is good, but the bioavailability is often reduced due to an extensive first-pass metabolism. Because no SERM has been administered by the intravenous route to humans, the exact bioavailability of any of these drugs has not been evaluated properly. Thus, we have to rely on indirect evidence. While the absorption of tamoxifen, droloxifene, toremifene, raloxifene and idoxifene is good an extensive first-pass metabolism due to glucuronidation followed by biliary excretion may reduce the bioavailability of tamoxifen, droloxifene and raloxifene. On the contrary, first pass metabolism seems to be low for compounds like toremifene and idoxifene.
MEMBERS AND USES4, 5, 9
SERMs are used dependent on their pattern of action in various tissues:
Table no. 1: Members and Uses
Used in anovulation
Other members include afimoxifene, arzoxifene and bazedoxifene. Some SERMs may be good replacements for hormone replacement therapy (HRT), which had been commonly used to treat menopause symptoms until the publication of wide scale studies showing that HRT slightly increases the risk of breast cancer and thrombosis. Some of the above agents still have significant side-effects which contraindicate widespread use.
Estrogenic compounds span a spectrum of activity ranging from: full agonists (agonistic in all tissues) such as the natural endogenous hormone estrogen mixed agonists/antagonistic (agonistic in some tissues while antagonist in others) such as tamoxifen (a SERM) pure antagonists (antagonistic in all tissues) such as Fulvestrant (ICI-182780). The mechanism of mixed agonism/antagonism may differ depending on the chemical structure of the SERM, but for at least for some SERMs, it appears to be related to (1) the ratio of co to co-repressor proteins in different cell types and (2) the conformation of the estrogen receptor induced by drug binding which in turn determines how strongly the drug/receptor complex recruits co-activators (resulting in an agonist response) relative to co-repressors (resulting in antagonism). For example, the prototypical SERM tamoxifen acts as an antagonist in breast and conversely an agonist in uterus. The concentration of steroid receptor co-activator 1 (SRC-1; NCOA1) is higher in uterus than in breast, therefore SERMs such as tamoxifen are more agonistic in uterus than in breast. In contrast, raloxifene behaves as an antagonist in both tissues. It appears that raloxifene more strongly recruits co-repressor proteins and consequently is still an antagonist in the uterus despite the higher concentration of co-activators relative to co-repressors.
Figure 2: Decision points that a selective estrogen receptor modulator (SERM) must pass to modulate estrogen-like actions in a target tissue. A SERM can bind to either estrogen receptor (ER)-α or ER-β and the complexes can then recruit co-activators or co-repressors. The complexes might homo or heterodimerize and modulate genes by either a nontraditional pathway of protein–protein interactions via binding of Fos and Jun proteins to activating protein 1 (AP-1) or a traditional pathway of ER–DNA interaction via an estrogen-response element (ERE).
Because of the potential cancer and cardiovascular risks inherent in hormone pills containing estrogen and progesterone, scientists are working on the development of SERMs for postmenopausal women that can mimic the beneficial effects of estrogen without exerting any of its harmful effects. The ideal drug, of course, would be a SERM exhibiting the positive effects of estrogen on bones, heart and blood vessels, without exhibiting the potentially harmful effects of estrogen on the breast and uterus15.
The fact that tamoxifen blocks the action of estrogen in breast tissue while mimicking the action of estrogen in the uterus means that it functions as a SERM, selectively blocking or stimulating the estrogen receptors of different target tissues. In addition to acting like estrogen in the uterus, tamoxifen resembles estrogen in its ability to lower LDL cholesterol levels. And in postmenopausal women, tamoxifen also resembles estrogen in its ability to preserve or increase bone density. Thus, aside from its tendency to increase the risk of uterine cancer, tamoxifen has a number of potentially beneficial properties. As a result, scientists have been actively working on the development of other SERMs that might exhibit some of the beneficial properties of tamoxifen without sharing its potentially harmful effects16.
Breast cancer is the most common form of cancer among women in the United States , with 180 000 new cases diagnosed annually and in the year 2000 alone there were more than 40 000 deaths. It is thought that estrogen has a role in the pathogenesis of many forms of neoplastic and non-neoplastic diseases, including breast cancer, endometrial cancer, endometriosis and uterine fibroids. Under normal circumstances, estrogen binds to the ER to activate gene transcription. Improper or excessive signaling by estrogen can lead to the development of cancer. Tamoxifen was the first SERM to be utilized in the treatment of metastatic breast cancer, with clinical use beginning in the 1970s. Over the past 25 years, tamoxifen has evolved as an agent used in all stages of breast cancer. Tamoxifen is most effective in ER-positive breast cancers. The Early Breast Cancer Trialists’ Collaborative Group’s findings were that adjuvant use of tamoxifen increases the 10-year survival of women with ER positive tumors and in women whose ER status is unknown. Although tamoxifen has been very successful in treating breast cancer, it is associated with insidious side effects, such as thromboembolic events, vasomotor symptoms and an increased risk of developing endometrial cancer and cataracts . Since then, researchers have worked to develop new SERMs with no estrogenic activity on the uterus and with fewer side effects.
The triphenylethylene antiestrogen toremifene has been approved by the FDA for the treatment of advanced breast cancer in postmenopausal women. The biologic effects of this SERM in postmenopausal women are similar to those of tamoxifen. Since toremifene has similar efficacy to that of tamoxifen as a first line endocrine therapy in the treatment of ER positive metastatic breast cancer, limited use has been seen in the United States. Furthermore, other hormonal agents such as aromatase inhibitors are also indicated as first line therapies for advanced breast cancer, limiting the use of toremifene. Although toremifene may be advantageous as an alternative to adjuvant tamoxifen therapy of breast cancer, it has not yet been approved by the FDA as an adjuvant therapy.
Raloxifene is currently being used clinically to treat and prevent osteoporosis. It does, however, act as an ER antagonist in breast tissue and it has been studied as an alternative to tamoxifen in the treatment of metastatic breast cancer. Preclinical studies found that raloxifene provided no advantage over tamoxifen in treating postmenopausal women with advanced breast cancer. Furthermore, in cases where the cancer became refractory to tamoxifen therapy, raloxifene conferred no additional antitumor activity and thus it was never pursued as a breast cancer therapy. However, since tamoxifen was found to increase the risk of endometrial cancer, there has been a renewed interest in raloxifene especially since postmenopausal women currently taking raloxifene for osteoporosis may harbor clinically undetected breast cancer. Therefore, a trial was designed to assess the efficacy of raloxifene in women with advanced breast cancer. The study included postmenopausal women with metastatic breast cancer without any prior systemic treatment. The results of this study were disappointing; only 33% of participants showed clinical benefit. Due to the low efficacy, raloxifene has not been pursued as a treatment for advanced breast cancer; rather, it is gaining new attention as a prophylactic therapy to prevent breast cancer in high-risk women.
The agonist properties of tamoxifen and other SERMs can contribute to an increased risk of endometrial carcinoma and might contribute to the development of resistance in tumor cells. Ideally, pure antiestrogens might combat these difficulties. The development of pure antiestrogens was pursued with the production of steroidal analogues of estrogen with bulky side chains at either the 7 or 11 position of estradiol. One of these drugs, Fulvestrant (Faslodex, AstraZeneca Pharmaceuticals and Wilmington, DE) has recently been approved for use in advanced breast cancer.41 Fulvestrant is approved for the treatment of metastatic breast cancer. The drug has notable efficacy in tamoxifen-refractory disease. In addition; the drug has demonstrated equivalent or superior activity when compared with anastrozole in the metastatic setting.
The complex pharmacology of SERMs is slowly being understood and this has already resulted in the discovery and development of new SERMs that act as antiestrogens on breast and endometrium while having estrogenic effects on bones, the lipid profile and the central nervous system. Several new SERMs are currently being tested in clinical trials such as LY353381 (arzoxifene), EM-652 and CP-336,156 and their structures are very similar to known SERMs. The true breakthrough could occur when ER-α and ER-β are modulated independently with receptor-specific agents. Some progress is being made in this area, but it might be some time before the toxicological consequences of new agents are understood. Nevertheless, the SERM concept of target site specificity has already spread to other members of the nuclear receptor superfamily [e.g. selective PPARγ modulators (SPARMs)] to make this a broad new concept in medicine.
The excess of research is directed towards the development of newer chemical entities in treatment of cancer. Which is proven to be most fatal disease of 20th century? The chemoprevention with lesser side effect is of major concern for the researchers engaged in the development of NCEs in treatment of cancer. SERMs may be considered as path for further developments in this particular area of research especially in treatment of breast cancer. Thus with further development in SERMs these agents can be explored as a candidate in treatment of breast cancer.
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