Oh

NMe2

Figure 3. Structures of SERMs (tamoxifen and raloxifene) and the SERD fulvestrant in comparison to estradiol.

Figure 3. Structures of SERMs (tamoxifen and raloxifene) and the SERD fulvestrant in comparison to estradiol.

The majority of breast cancers express androgen receptors at a level >10 fmol/mg (66), and androgens were used for breast cancer therapy before implementation of contemporary treatment options (67). The response rate however was low, and androgens cause disturbing side effects, like hirsuitism.

Estrogens administered at high doses (in general DES 15 mg daily) was a frequently used treatment option for pre- as well as postmenopausal breast cancer before tamoxifen came into clinical use. Thus, in a randomized trial, Ingle et al. revealed similar efficacy for estrogens and tamoxifen administered for metastatic breast cancer (68). It should be emphasized that the estrogen doses used for breast cancer therapy were at least a magnitude higher compared to doses used for hormone replacement, and the effects achieved with this strategy should never be taken as an argument in favor of safety regarding hormone replacement therapy for breast cancer patients. While the mechanism by which estrogens achieve these antitumor effects are not understood, some experimental data are of interest. It is well known that estrogen-induced growth stimulation of MCF-7 cells in vitro is expressed as a "bell-shaped" curve (69, 70). Thus, escalating the estrogen concentration above the optimal concentration for cell growth actually inhibits cell growth. In an elegant experiment, Masamura et al. (70) created an estrogen "hypersensitive" MCF-7 cell line by growing cells exposed to low hormone concentrations over time. These "LTED" cells (long-time estrogen deprived cells) achieved optimal growth stimulation by estradiol at a concentration about 0.01-0.1% the concentration needed for regular MCF-7 cells. Most importantly, in the LTED cells the whole "bell-shaped" growth stimulation curve moved to the left, meaning that estradiol at a concentration stimulating growth of regular MCF-7 cells inhibited growth of the LTED cells. Based on these findings, we designed a pilot study treating patients becoming resistant to multiple endocrine regimens, including potent third-generation aro-matase inhibitors, with DES 15 mg daily (71). Our finding that 10 out of 32 patients obtained a partial remission, confirmed many of these tumors still to be hormone sensitive, and was consistent with the hypothesis that resistance to treatment with aromatase inhibitors at least in some cases, may develop through "hypersensitivity" of the cells to estradiol.

Natural Cures For Menopause

Natural Cures For Menopause

Are Menopause Symptoms Playing Havoc With Your Health and Relationships? Are you tired of the mood swings, dryness, hair loss and wrinkles that come with the change of life? Do you want to do something about it but are wary of taking the estrogen or antidepressants usually prescribed for menopause symptoms?

Get My Free Ebook


Post a comment