Triphenylethylene structures similar to tamoxifen(Drug information on tamoxifen) (Nolvadex) were first used in the 1940s, but in comparison to synthetic and natural estrogens(Drug information on estrogens) used at that time, they were not particularly potent antitumor agents. [1,2] Tamoxifen was introduced into the clinic in 1969. Because of its much improved toxicity profile over the estrogens and androgens in use at that time, it rapidly gained acceptance as the endocrine treatment of choice for advanced breast cancer and subsequently as adjuvant therapy.[3-5]
Three different strategies have been used to develop new antiestrogens: (1) chemical alteration of the triphenylethylene ring of tamoxifen, (2) production of new nonsteroidal ring structures (eg, the benzothiophenes), and (3) production of steroidal estradiol(Drug information on estradiol) analogs with pure antiestrogenic activity (Figure 1).
All of the nonsteroidal antiestrogens discussed in this article are partial estrogen agonists to differing degrees. In contrast, the steroidal pure antiestrogens lack intrinsic estrogenic activity and appear to have a somewhat different mechanism of action. Although both types of compounds bind to the estrogen receptor (ER), the tamoxifen analogs allow partial activation of estrogen receptors, permitting transcription of some estrogen-regulated genes, whereas the steroidal antiestrogens appear to completely inhibit transcriptional activity via the estrogen receptor.
The six nonsteroidal antiestrogens shown in Figure 1 are either marketed or in clinical trials. All but one, raloxifene(Drug information on raloxifene), are based on the triphenylethylene molecule. In addition, pure steroidal antiestrogens (ICI 164,384 and ICI 182,780) have been developed in order to produce a state of complete estrogen deprivation. The overall goal for the development of new antiestrogens is to increase their efficacy and safety (Table 1).
This last characteristic is important because many women taking these agents are treated for long periods with adjuvant therapy. Since most breast cancer patients are unlikely to receive hormone replacement therapy due to fear of disease recurrence, new endocrine breast cancer agents with an improved side-effect profile and favorable effects on bone mineral density and the cardiovascular system would be highly valuable.
The purpose of this review is: (1) to describe the current status and ultimate potential of the nonsteroidal antiestrogen agents and (2) to introduce a new class of pure steroidal antiestrogen agents.
Tamoxifen has gained wide clinical acceptance, first for metastatic breast cancer and then for adjuvant therapy. Currently, tamoxifen is being studied for the chemoprevention of breast cancer in healthy women at high risk for the disease. The use of tamoxifen has expanded over the years because of its efficacy in prolonging overall and disease-free survival as well as reducing the incidence of contralateral breast cancer. Because tamoxifen is a mixed estrogen agonist and antagonist, it has been shown to have positive, estrogenic effects on bone and the cardiovascular system while maintaining antitumor activity via its antiestrogenic effects. The estrogenic activity of tamoxifen has been associated with a proliferative effect on the endometrium and a two- to threefold increase in the risk of endometrial carcinoma. This association has stimulated interest in the discovery of new antiestrogens with no uterotropic activity. The methods for evaluating these compounds are shown in Table 2.
Toremifene (Fareston) differs from tamoxifen by only a single chlorine atom (see Figure 1). Although it produces different metabolites due to the stability of the chlorine atom, toremifene(Drug information on toremifene) has a pharmacologic profile similar to tamoxifen.
Toremifene displaced [3H]estradiol binding to estrogen receptors by 50% at a concentration of 0.5 mmol/L. In the ER-positive human breast carcinoma cell line MCF-7, toremifene showed a pattern of activity similar to tamoxifen: growth inhibition at low concentrations and oncolytic activity at high concentrations. A concentration of 5 × 10-6 M toremifene killed all MCF-7 cells within two days. The activity of toremifene appears to be estrogen-dependent; growth inhibition of MCF-7 cells at concentrations less than 10-6 M can be reversed with estradiol.
Against dimethylbenzanthracene (DMBA)-induced rat mammary cancer, toremifene and tamoxifen showed similar antitumor activity; the one difference was that 45 mg/kg tamoxifen was toxic to the rat, whereas 45 mg/kg toremifene showed an antitumor effect.
In the rat uterus, the estrogenic effects of toremifene appear to be lower than tamoxifen at low and moderate concentrations; however, the maximum estrogenic response was similar. Toremifene has also demonstrated estrogenic effects on human endometrial tissue in postmenopausal breast cancer patients, including increasing endometrial thickening and proliferation.
Unlike tamoxifen, toremifene did not produce liver tumors in rats at doses up to 48 mg/kg for one year.
Toremifene has been studied in a comparative trial with tamoxifen in 648 perimenopausal or postmenopausal women with metastatic breast cancer (hormone receptor positive or unknown receptor status). The three treatment arms consisted of tamoxifen (20 mg/d), toremifene (60 mg/d), or toremifene (200 mg/d). In the intent-to-treat analysis, the frequency of objective response (complete or partial) was 19% for tamoxifen, 21% for 60-mg toremifene, and 23% for 200-mg toremifene (P not significant between treatments). The median response durations were 19.1 months, 16.9 months, and 18.4 months, respectively (P not significant between treatments). Likewise, there were no significant differences among the three treatments in the median time to progression or median overall survival.
Overall, the type and frequency of adverse effects were similar among the three groups, including the incidence of tumor flare and thromboembolic and cardiac events; however, the 200-mg toremifene dose was associated with a greater frequency of elevated aspartate aminotransferase (AST) levels and nausea.
At this time, there does not appear to be any benefit of toremifene over tamoxifen. The clinical experience with toremifene will need to be expanded substantially to determine if there is any benefit of the drug with respect to rare adverse events such as endometrial cancer.
Droloxifene (3-hydroxytamoxifen) is currently undergoing clinical trials in advanced breast cancer. Unlike tamoxifen, droloxifene is itself the active moiety and thus does not require metabolism for activation. Droloxifene shows a higher binding affinity for ER compared with tamoxifen. The IC50 for the displacement of 17-beta-estradiol from ER is 1 × 10-8 M. In rats, droloxifene exhibits higher antiestrogenic activity and lower estrogenic activity than tamoxifen.
Droloxifene is more effective than tamoxifen in inhibiting the growth of ER-positive breast cancer cells, even at therapeutic concentrations (0.1 to 0.4 mM), and its activity is related to ER content. Interestingly, short-term (1-hour) exposure to droloxifene in vitro produced maximum growth inhibition, leading investigators to conclude that the agent may be suitable for intermittent therapy. Moreover, droloxifene produced a greater antitumor effect than tamoxifen against DMBA-induced breast tumors in rats. Droloxifene (at doses up to 200 mg/kg/d for 6 months or doses up to 90 mg/kg/d for 24 months) is not hepatocarcinogenic in the rat.
A large phase II trial of droloxifene was conducted in centers located in Europe, Canada, and Brazil. The purpose of the study was to compare three daily doses (20 mg, 40 mg, and 100 mg) in postmenopausal women with advanced breast cancer. Eligible patients had no prior exposure to systemic hormonal therapy and had positive or unknown hormone-receptor status; of 369 randomized patients, 268 were evaluable for response.
Complete or partial responses were seen in 30% of the 20-mg group, 47% of the 40-mg group, and 44% of the 100-mg group. The differences were significant between the 20-mg group and the 40-mg group (P = .02) and between the 20-mg group and the 100-mg group (P = .04). Half of the responses were seen within the first two months of starting treatment.
The median duration of response was 12 months for 20 mg, 15 months for 40 mg, and 18 months for 100 mg. Again, the 40-mg (P = .02) and the 100-mg (P = .01) groups had significantly better results than the 20-mg group.
Side effects reported by more than 20% of patients included hot flashes, lassitude, and nausea; the frequency of these effects did not appear to be dose related. Thromboembolic events did not occur more frequently than with other antiestrogens.
Issues that remain to be resolved for droloxifene include its effects on the uterus, bone, and the cardiovascular system as well as its potential for cross-resistance with tamoxifen. Droloxifene has been shown to have estrogenic effects on bone in the rat, and clinically, has produced decreases in plasma cholesterol without affecting cholesterol synthesis. Although these results look promising, as with toremifene, droloxifene's ultimate clinical profile will only be determined in trials comparing it with tamoxifen.
Raloxifene is a benzothiophene derivative with a high binding affinity for ER, reportedly 2.9-fold greater than that of estradiol. In the rat, raloxifene has exhibited antiestrogenic activity in the breast and uterus and estrogen agonist activity on bone and lipids.
In contrast to tamoxifen, raloxifene showed a lack of uterotropic effect after four days of treatment in ovariectomized rats. Near complete antagonism of estrogen-induced uterotropic activity was observed at 1 mg/d. Moreover, three days of raloxifene was able to block the uterotropic action of estradiol for 10 subsequent days. Raloxifene was unable to reverse the uterotropic response to tamoxifen. Raloxifene dose-dependently inhibited estrogen-stimulated proliferation of MCF-7 cells.
Sato et al compared the effects of raloxifene and tamoxifen on bone, cholesterol, and the uterus in six-month-old, ovariectomized rats. The effect of raloxifene on bone mineral density was dose-dependent, with an ED50 of 0.3 mg/kg/d (35 days of treatment), while the ED50 for tamoxifen was 0.1 mg/kg/d. At doses of 0.1-10 mg/kg, raloxifene dose-dependently reduced cholesterol levels to 51% to 62% of ovariectomized controls. The results were similar for tamoxifen. In contrast, uterine epithelial thickness increased by 250% with tamoxifen therapy, compared with only 60% seen with raloxifene.
Raloxifene (100 mg orally, two times a day) was studied in 14 patients with disseminated breast cancer refractory to tamoxifen. There was one minor response in a patient with soft-tissue disease and in five patients with stable disease. Side effects included hot flashes (n = 4), fatigue (n = 3), leg cramps (n = 1), and mild nausea (n = 3).
Although the antitumor activity of raloxifene needs further evaluation, the drug may have a role in the prevention of osteoporosis in postmenopausal women. In this population, raloxifene doses 50 or more mg/d have significantly reduced total serum and low-density lipoprotein (LDL) cholesterol as well as serum markers of bone turnover (eg, osteocalcin, alkaline phosphatase).