Tamoxifen-stimulated breast

Tonetti, D. A., and Jordan, V. C. 1997. The role of estrogen receptor mutations in tamoxifen-stimulated breast cancer (review). J. SteroidBiochem. Mol. Biol. 62 119-128. 

Toremifene (Fareston , chlorotamoxifen Figure 5.15) has been thoroughly investigated in the laboratory [269-272] and has antitumor activity in carcinogen-induced rat mammary cancer, but is less potent than tamoxifen [272-274]. Toremifene has been tested extensively in phase I—III clinical trials [275-278] and has been approved for use in postmenopausal women with metastatic breast cancer [279]. As predicted from the reduced potency in animal studies, the dose required for activity is 60 mg of toremifene daily (tamoxifen is used at 20 mg daily). The side-effects are similar to those of tamoxifen and, as with tamoxifen, the responses are observed in ER-positive tumors. However, because adjuvant therapy with tamoxifen is standard throughout the world, issues of cross-resistance of tamoxifen and toremifene are important considerations for the use of toremifene in recurrent breast cancer. Laboratory studies by Osborne et al. [280] have demonstrated that toremifene-stimulated tumors can develop from MCF-7 breast cancer cells transplanted into athymic mice. Toremifene is cross-resistant with tamoxifen in tamoxifen-stimulated breast cancer in the laboratory [281]. Similarly, cross-over clinical trials demonstrate that there is little possibility of a second response to toremifene after tamoxifen failure [282, 283]. 

Osborne, C.K., Jarman, M., McCague, R., Coronado, E.B., Hilsenbeck, S.G. and Wakeling, A.E. (1994) The importance of tamoxifen metabolism in tamoxifen-stimulated breast tumor growth. Cancer Chemotherapy and Pharmacology, 34, 89-95. 

Schafer, J.M., Lee, E.S., Dardes, R.C., Bentrem, D., O Regan, R.M., De Los Reyes, A. and Jordan, V.C. (2001) Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts. Clinical Cancer Research, 7, 2505-2512. 

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

Stimulated by the need for an improved therapy for breast cancer, considerable efforts have been devoted to the synthesis of compounds that would exert pure antiestrogenic activity in the mammary gland and uterus. As mentioned above, while tamoxifen has beneficial effects on breast cancer, it clearly acts as an estrogen agonist in the endometrium, leading to an increased rate of endometrial carcinoma in women taking tamoxifen under chronic conditions. Moreover, it is most likely that a pure antiestrogen will have beneficial effects superior to those of tamoxifen in breast cancer prevention and treatment. 

A 5-year course of tamoxifen treatment provides protection superior to 1-2 years of treatment. Currently, 5 years of adjuvant tamoxifen is recommended to be optimal, since extending treatment beyond 5 years provides no further improvement [137,138], There are reports of tamoxifen-stimulated tumor growth occurring during the treatment of advanced (metastatic stage IV) breast cancer [139,140], but there is currently no evidence that extending tamoxifen beyond 5 years of adjuvant therapy increases the risk of tumor recurrence. Critically important, the protective effects of tamoxifen on breast cancer recurrence and mortality are persistent long after tamoxifen therapy is stopped. A meta-analysis of 15 years of follow-up of 10,386 women shows that 5 years of adjuvant tamoxifen in ER-positive disease versus not... 

Wolf, D.M. and Jordan, V.C. (1994) Characterization of tamoxifen stimulated MCF-7 tumor variants grown in athymic mice. Breast Cancer Research and Treatment, 31, 117-127. 

Eulvestrant binds to ERa and ER/3 with an affinity comparable to estradiol but represses transactivation. Eulvestrant also stimulates the proteolytic degradation of ERa, which may explain its efficacy in tamoxifen-resistant breast cancer. 

Droloxifene (3-hydroxy-tamoxifen) behaves as an estrogen agonist in bone tissue and several lipid and coagulation markers in castrated rat models and does not show stimulation of the endometrial epithelium in preclinical studies (Ke et al. 1997). Endometrial stimulation has, however, been observed in clinical trials, which, together with the fact that as an estrogen agonist it is ten times less potent than tamoxifen in bone tissue and lipid metabolism (Hendrix et al. 2001) and that in a recent head-to-head comparison with tamoxifen droloxifene was demonstrated not to be superior in any parameter of breast cancer treatment efficacy (Buzdar et al. 2002), has resulted in cancellation of its clinical development. 

When used in tumor cells, fulvestrant was initially described as a potent, competitive growth inhibitor of ER-positive, human breast cancer MCF-7 cells, whose growth is stimulated by estradiol. The compound was ineffective in tumor cell lines without ER, such as MDA-MB-231. The inhibitory effects were more pronounced with fulvestrant than with tamoxifen in the same cell line (Wakeling et al. 1991). 

The evidence that tamoxifen was able to exert estrogenic effects on several tissues like the bone (Love et al. 1992) opened the door to the concept of SERMs, which is explained in detail in Chaps. 2 and 3 of this book. The mechanisms of action of these substances on ERs is explained in detail in Chap. 3. However, it is pertinent to comment on some special aspects of its action on mammary cancer cells. IGF-1 is a key element in growth control of malignant breast cells through endocrine and paracrine pathways. Tamoxifen and its active metabolite are able to inhibit IGF-l-stimulated growth (Jordan... 

In a prospective study in 77 consecutive women with postmenopausal breast cancer scheduled to start endocrine treatment for breast cancer, using either tamoxifen or an aromatase inhibitor tamoxifen treatment significantly increased endometrial thickness and uterine volume after 3 months (24). In additional, tamoxifen induced endometrial cysts and polyps and increased the size of pre-existing fibroids. In contrast, aromatase inhibitors did not stimulate endometrial growth and were not associated with endometrial pathology. Furthermore, they reduced endometrial thickness and uterine volume in patients who had previously taken tamoxifen. 

Estrogen receptor blockers (fulvestrant, tamoxifen) can likewise help prevent and treat breast and uterine cancers that are stimulated by estrogen.37 Fulvestrant (Faslodex) is classified as a pure antiestrogen... 

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