Hormones antiestrogen

A stmcturally related series of phenyfiiydrazones resulted ia the selection of compound A-007 [2675-35-6] (DEKK-TEC)(37) for the treatment of hormone-dependent tumors. A-007 is an antiestrogen that, ia contrast to tamoxifen, demonstrated inhibitory activity both ia the presence and absence of estradiol ia ZR-75-1 estrogen-dependent human breast cancer cells, and afforded more protection than tamoxifen ia the 7,12-dimethylbenz[i7]anthracene... 

The area of nonsteroidal antiestrogens along with other classes of nonsteroidal antagonists of sex-steroid hormone action has been reviewed to 1986, and these compounds have been grouped by chemical stmcture as a basis of classification rather than any biochemical or biological test system utilized to assess antagonist activity (46). 

Hormonal therapies that have been studied in the treatment of primary or early breast cancer include antiestrogens, oophorectomy, ovarian irradiation, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors. 

Tamoxifen is the antiestrogen of choice in premenopausal women whose tumors are hormone-receptor positive, unless metastases occur within 1 year of adjuvant tamoxifen. Maximal beneficial effects do not occur for at least 2 months. In addition to the side effects described for adjuvant therapy, tumor flare or hypercalcemia occurs in approximately 5% of patients with MBC. 

Fig. 1.5. Activation of the native receptor by thehormone. The hormone-receptor interaction determines a very strong bond that attracts distant amino acid residues, which alters the three-dimensional structure of the receptor. As a consequence, the receptor loses its affinity for the proteins that were originally close but that no longer find their zones of contact with the receptor. Simultaneously, the receptor reorganizes other hormone-dependent zones it acquires dimerization capacity and exhibits a capacity to bind to DNA and to transcription factors. The interaction with antiestrogens also produces a conformational change, which can give rise or not to the formation of dimers, in any case with a different conformation...

EM-800 (SCH-57050) and its active metabolite EM-652 (acolbifene, SCH-57068), are highly potent antiestrogens in human breast and uterine cancer cells in vitro as well as in vivo in nude mice and are currently undergoing clinical trials in the treatment of hormone-dependent breast cancer and endometrial cancer (Labrie et al 1999). Acolbifene shows a higher capacity of binding to... 

Rao US, Fine RL, Scarborough GA (1994) Antiestrogens and steroid hormones substrates of the human P-glycoprotein. Biochem Pharmacol 48(2) 287-292... 

Finally, estradiol induced a response in the luciferase activity of MVLN transfected cells. The hormone increased three-fold the basal level of enzymatic activity (Fig. 7.3.2). The luciferase activity of each experiment was normalised to the steroid-free control cultures to correct for differences in the initial seeding density. The activity induced by the antiestrogen RU 58 668 was lower than the response to the control. 

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