China
Africa
Explore chapters and articles related to this topic
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Although formestane proved to be an effective and safe aromatase inhibitor in the clinic, its use significantly declined due to the development of a number of safe and effective orally active aromatase inhibitors that were more convenient to administer. Although it is still available for the treatment of ER+ breast cancer in postmenopausal women, it is apparent that there is a growing illegal use by male body builders and athletes to reduce the estrogenic side effects of anabolic steroids, to increase muscle definition while dieting and to improve fat loss.
Individualization of Endocrine Therapy in Breast Cancer
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Amelia B. Zelnak, Ruth M. O’Regan, Clodia Osipo
An alternate strategy to endocrine therapy, which specifically inhibits binding of E2 to the ER, is to inhibit the production of E2 by blocking the cytochrome p450 aromatase enzyme, the rate-limiting enzyme that converts androgens (i.e., testosterone and androstenedione) to estrogens (i.e., E2 and estrone) in the adrenal gland, surrounding stroma, and adipose tissue of the breast tumor. The main drugs of this type are aromatase inhibitors, which include Type I (steroidal) or Type II (nonsteroidal) (Fig. 2). Steroidal inhibitors are competitive-substrate mimics of androstenedione. These include formestane and exemestane, which are irreversible inhibitors that bind with high affinity to the binding site of aromatase and are converted to a covalently bound intermediate. Nonsteroidal inhibitors include the first-generation aromatase inhibitor aminoglutethimide and the second-generation compounds anastrozole and letrozole. All nonsteroidal aromatase inhibitors act by binding reversibly to the enzyme and competitively inhibiting binding of the substrate androstenedione. The benefits of using aromatase inhibitors over tamoxifen are believed to be the complete deprivation of E2 and thus better efficacy for ERα-positive breast cancer (51). Recent clinical data have clearly demonstrated that anastrozole (52), letrozole (53), and exemestane (54) are more effective than tamoxifen as first-line treatments in patients with metastatic breast cancer. On the basis of clinical results (52,53), currently both anastrozole and letrozole are approved by the Food and Drug Administration for first-line treatment of postmenopausal, ERα-positive advanced breast cancer. The data from advanced breast cancer trials provided the rationale to perform large-scale clinical trials to determine whether there is an advantage of using aromatase inhibitors over tamoxifen in the adjuvant setting. The anastrozole, tamoxifen, and the combination of anastrozole and tamoxifen (ATAC) trial has sufficient follow-up data to confirm that anastrozole is superior to tamoxifen as a first-line adjuvant therapy in ERa-positive breast cancer with regard to disease-free survival and incidence of contralateral breast cancer (55). The Breast International Group (BIG) 1–98 study demonstrated a similar improvement in event-free survival to confirm that letrozole is superior to tamoxifen as first-line adjuvant hormonal therapy (56). Other trials have demonstrated an improved outcome for postmenopausal patients with early-stage breast cancer treated with two to three years of tamoxifen, followed by an aromatase inhibitor, compared with five years of tamoxifen (57,58). The BIG 1–98 trial will help to determine whether these sequencing/switching approaches are equivalent to upfront aromatase inhibitors.
Recent advances in computational design of potent aromatase inhibitors: open-eye on endocrine-resistant breast cancers
Published in Expert Opinion on Drug Discovery, 2019
Angelo Spinello, Ida Ritacco, Alessandra Magistrato
A breakthrough in AIs’ development was the discovery of formestane (FMS), 4-hydroxyandrostenedione, as the first steroidal AI active via irreversible inhibition mechanism [46], displaying limited side effects. Although requiring intramuscular injection for administration, FMS was one of the most promising second-generation inhibitors and was an object of several clinical trials [47–49]. To the same generation of AIs belong Fadrozole (FDZ), a competitive and reversible inhibitor, displaying a high potency (measured as IC50) and selectivity towards HA as compared to AGT [50,51]. Unfortunately, FDZ was shown to induce aldosterone suppression. This limited its use to doses able to produce only a 90% inhibition [52]. Thus, in spite of its initial success and its clinical approval in Japan, FDZ never reached an extensive clinical use [53]. As well, no other molecules among the second-generation AIs were approved as drugs.
Black cohosh efficacy and safety for menopausal symptoms. The Spanish Menopause Society statement
Published in Gynecological Endocrinology, 2022
Camil Castelo-Branco, Concepción Navarro, Estanislao Beltrán, Fernando Losa, Marta Camacho
In in vitro assays on tamoxifen-treated MCF-7 cells, the addition of CR extract showed a synergistic effect with tamoxifen, reducing tritiated thymidine uptake in a dose-dependent manner [36]. Similarly, in cultures of MDA-MB-453 (ER-negative, Her-2 positive) cells, CR showed synergistic effects with chemotherapeutics such as paclitaxel and doxorubicin [49], an effect similar to that observed by Rockwell et al. [53] in mice breast cancer EMT6 cells (ER-, RP-) that showed synergistic action with doxorubicin. In another study using a rat mammary carcinoma model treated with formestane, the addition of CR extract did not modify the inhibition of tumor growth produced by the aromatase inhibitor [54].
Benefit–risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John’s wort in breast cancer patients
Published in Climacteric, 2019
X. Ruan, A. O. Mueck, A.-M. Beer, B. Naser, S. Pickartz
The well-established dimethylbenz(a)-anthracene-induced estrogen receptor-positive mammary tumor model in Sprague Dawley rats was used in most in-vivo studies47–50. In contrast to mestranol-treated rats, no stimulation of tumor growth was found in animals treated with iCR in doses up to 100-fold the human therapeutic dose47. No significant differences to vehicle control were observed, but a trend toward reduced tumor growth was seen. Prolactin, follicle stimulating hormone, luteinizing hormone, organ weight, and endometrial proliferation remained unaffected by iCR47. Compared to vehicle control, iCR treatment, starting from prepubertal age, resulted in marked retardation of tumor growth and a significantly prolonged life span48. Combination of iCR with tamoxifen increased the incidence of tumor-free rats from 20 to 50% with a pronounced retardation of neoplastic growth49. Necropsy found the individual tumor burden to be reduced by 50%. Concomitant iCR application neither affected serum estradiol nor the antineoplastic effects of the aromatase inhibitor (AI) formestane50. One study used a transgenic MMTV-neu mouse model, in which breast cancer is promoted by mouse mammary tumor virus (MMTV)51. Mice bear the rat oncogene neu, the rodent homolog of human epidermal growth factor receptor 2 (HER2); thus, this artificial model generates spontaneous, highly progressive breast cancer with rapidly developing lung metastases. No differences were detected in the incidence and onset of breast cancer between iCR and control. Incidence of lung metastases was increased; however, neu transgene was not upregulated in the treatment group. Estrus cycling and hormone levels were not modified. No uterotrophic activity occurred.