Tamoxifen compounds

For the purposes of this article, antiestrogens are compounds that counteract the biological activity of estrogens at the receptor level. In the late 1970s, there were no steroidal antiestrogens in widespread clinical use. Clomiphene [911 -45-5]( ) and tamoxifen/7(954(9-25 -/7(9) were nonsteroidal antiestrogens that had been employed for the treatment of female infertility and breast cancer, respectively. 

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... 

Selective estrogen receptor modulators (SERMs) are synthetic compounds with partially agonistic and partially antagonistic estrogenic properties. In bone, SERMs inhibit bone resorption via the mechanisms known for estrogens. Major SERMs are tamoxifen, a triphenylethylene compound, and raloxifene. In postmenopausal women, the latter has been shown to prevent bone loss and to reduce fracture risk by 40%. 

Zajchowski et al. [107] showed comparison of expression profiles between 38 different estrogen receptor-modulating compounds. An intial study was run based on the results of profiling of 24 combinations of cells and genes with estrogen, tamoxifen, raloxifene and ICI 164384 (a pure ER antagonist). Using the optimized assay panel derived from these studies, the 38 compounds were then profiled and classi-... 

The application of organometallic complexes of the other group 8 elements, iron and osmium, in anticancer drug design has until recently been almost exclusively focused on iron, with the ferrocenyl derivative of tamoxifen (ferrocifen) being the most prominent example (104). Organometallic osmium compounds have been little explored in this respect. 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Fig. 4.2. Effects of triphenylethylene SERMs on spontaneous and depolarization-induced contractions in visceral smooth muscle. Tamoxifen (a) and ethylbromide tamoxifen (EBTx, b) rapidly and reversibly inhibit spontaneous peristaltic activity in duodenal muscle. Both compounds also inhibit depolarization-induced tonic contraction of uterine muscle (c). The inhibition of L-type voltage-dependent calcium channels underlies the relaxing effects illustrated here. Drugs concentrations were 10 xM in all cases. %RA percent of activity related to maximal activity...

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Nonsteroidal SERMs can also amplify signal-induced Ca2+ surges by inhibiting Ca2+-calmodulin-dependent membrane (Ca2+ + Mg2+)-ATPase. For instance, in synaptic plasma membranes and red cell membrane ghosts, tamoxifen and other triphenylethylene compounds (but not estradiol) have been... 

Wiseman H, Quinn P, Halliwell B (1993) Tamoxifen and related compounds decrease membrane fluidity in liposomes mechanism for the antioxidant action of tamoxifen and relevance to its anticancer and cardioprotective actions FEBS Lett 330( 1) 53—56... 

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 main potential utility of the pure antiestrogens is in the treatment of breast cancer. Several studies on their effects on the breast demonstrate both the pure antiestrogenic action of the tested compounds and their beneficial effects on breast cancer treatment. In experiments conducted in nude mice xenotrans-planted with two different human estradiol-dependent breast tumors, a single injection of fulvestrant provided an antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks (Wakeling et al. 1991). Additionally, RU 58668 was able to induce up to 30% disappearance of MCF-7 breast... 

Pure antiestrogens, which act by different mechanisms of action, probably are not affected by the mechanisms of tamoxifen resistance. As a result, those compounds might be a good choice as second-line hormonotherapy of breast cancer after failure of tamoxifen treatment, as has been reported in clinical... 

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