Tamoxifen ICI

Fulvestrant is a pure estrogen receptor antagonist that has been somewhat more effective than those with partial agonist effects in some patients who have become resistant to tamoxifen. ICI 164,384 is a newer antagonist it inhibits dimerization of the occupied estrogen receptor and interferes with its binding to DNA. It has also been used experimentally in breast cancer patients who have become resistant to tamoxifen. 

Estradiol tamoxifen, ICI Constitutive transactivation Tyr537Asn creates a receptor that displays... 

Tamoxifen, 4-hydroxytamoxifen, nafoxidine, 1 P-oestradiol and ICI 164,384 were all found to protect rat liver nuclei against Fe(III)-ascorbate-dependent lipid peroxidation (Wiseman and Halliwell 1994). The order of effectiveness of these compounds was 4-hydroxytamoxifen >17P-oestradiol > nafoxidine > tamoxifen > ICI 164,384. The idea of a protection by tamoxifen against the formation of the genotoxic reactive intermediates and products of lipid peroxidation in the nuclear membrane and thus of an anticarcinogenic benefit was later questioned Carthew etal. (2001) found a clear dose-response relationship of tamoxifen-induced DNA adducts in the rat liver and the subsequent increase in the development of liver cancer, with and without phenobarbital promotion. In the absence of phenobarbital promotion there was a threshold value for of tamoxifen-induced DNA adducts (180 adducts/10 nucleotides) and the subsequent induction of liver cancer. 

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-... 

O Regan RM, Cisneros GM, England GM, MacGregor JI, Muenzner HD, Assikis VJ, et al. (1998) Effects of the antiestrogens tamoxifen, toremifene, and ICI 182,780 on endometrial cancer growth. J Natl Cancer Inst 90 1552-1555... 

To illustrate the different actions of both groups of antiestrogens, Table 6.1 presents the tissue-specific effects obtained with the administration of type I (tamoxifen and raloxifene) and type II (ICI 164384 and fulvestrant) antiestrogens in preclinical studies. 

In the initial studies with pure antiestrogens, both ICI 164384 and fulvestrant inhibited cell growth and arrested the cell cycle in the Gi phase. These effects were two orders of magnitude more potent than those achieved with tamoxifen in the same experimental conditions (Wakeling and Bowler 1987). 

When studied in a model of human endometrial carcinoma, such as EnCa 101 tumors in athymic mice, ICI 164384 not only showed no stimulatory activity on tumor progression but also blocked the tamoxifen-stimulated growth of the tumor (Gottardis et al. 1990). 

Howell A, DeFriend D, Robertson J, Blarney R, Walton P (1995) Response to a specific antioestrogen (ICI 182780) in tamoxifen-resistant breast cancer. Lancet 345 29-30... 

The relevance attributed to oxidized lipids, and particularly oxidized LDL, in atherogenesis has precipitated interest in the ability of SERMs to this regard. Ex vivo experiments have confirmed that both tamoxifen and raloxifene exert some protection against the oxidation of LDL particles (Arteaga et al. 2003 Zuckerman and Bryan 1996) and that, interestingly, raloxifene is a more powerful antioxidant than tamoxifen or estradiol. It seems that this antioxidant effect is not mediated by the activation of the ER since pure antiestrogens like ICI 182780 and other SERMs like EM 652 have proven to have similar protective effects on LDL (Hermenegildo et al. 2002) (Fig. 9.4). 

Huynh HT, Poliak M (1993) Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antiestrogen ICI 182780. Cancer... 

Zhang JJ, Jacob TJ, Hardy SP, Higgins CF, Valverde MA (1995) Lens opacification by antioestrogens tamoxifen vs ICI 182,780. BrJ Pharmacol 115 1347-1348... 

Afzal I, Cunningham P, Naftalin RJ. 2002. Interactions of ATP, oestradiol, genistein and the anti-oestrogens, faslodex (ICI 182780) and tamoxifen, with the human erythrocyte glucose transporter, GLUT1. Biochem J 365 707-719. 

The tissue specificity of an estrogenic, antiestrogenic, or mixed estrogenic-antiestrogenic response can thus be explained by two different sites of DNA action of ERa and ERp. The classical ERE (Fig. 5A) binds both ER0C-E2 and ERP-E2, with a positive response in both cases (Fig. 6). With ERa or ER 3 and a reporter gene under the transcriptional control of an ERE, tamoxifen and raloxifene as well as ICI 164,384 inhibit the stimulatory effect ofE2 (Paech et al., 1997). 

When the reporter gene was controlled by an AP-1 instead of an ERE element, E2, DES (diethylstilbestrol), tamoxifen, and raloxifene as well as ICI 164,384 all stimulated transcription with ERa. When ER(3 was transfected instead of ERa, E2 and DES had an inhibitory effect, whereas the three antiestrogens exerted a stimulatory effect (Fig. 6). Most interestingly, E2 could reverse the stimulatory effect of raloxifene mediated by ER(3 and the AP-1 element in a dose-dependent manner. Although these experiments were performed in HeLa cells, it is relevant to mention that in human breast cancer MCF-7 and uterine cancer Ishikawa cells (Paech et al., 1997), ER 3 acting at an AP-1 element led to the same observations, namely stimulation by antiestrogens and inhibi-... 

Fig. 6. Specificity of the effect of 17P-estradiol (E2), diethystilbestrol (DES), tamoxifen, raloxifene, and ICI 164,384 on transcription induced by the ERE and AP-l-element ER-regulated genes (from Paech et al., 1997).

Comparison of the Effects of EM-652 and EM-800 with Those of ICI 164,384, ICI 182,780, Hydroxy tamoxifen, Tamoxifen, Droloxifene, Toremifene, and Hydroxytoremifene on Basal and E2-Induced Cell Proliferation in the T-47D Human Breast Cancer Cell Line... 

Since EM-800 is rapidly metabolized into the active compound EM-652 in intact cells, we compared the effect of increasing concentrations of the nonsteroidal antiestrogens EM-652 and EM-800 with those of hydroxytamoxifen and tamoxifen and of the steroidal antiestrogen ICI 164384 on basal and E2-induced cell proliferation in T-47D, ZR-75-1 and MCF-7 cells (Simard et al., 1997a). As illustrated in Fig. 20, a 10-day exposure to 0.1 nME2 increased the proliferation of T-47D cells 4.77-fold. This E induced stimulation of cell proliferation was competitively blocked by simultaneous incubation with EM-800, EM-652, hydroxytamoxifen, ICI 164,384, and tamoxifen at respective IC50 values of 0.148, 0.146, 0.522, 2.41, and about 100 nM. It can also be seen in Fig. 20 that none of these compounds affected basal T47-D cell proliferation when incubated alone. 

Fig. 20. Effect of increasing concentrations of EM-652, EM-800, ICI 164,384, 4 hydroxy-trans-tamoxifen (OH-TAM), or tamoxifen (TAM) on basal and E2-induced cell proliferation in T-47D human breast cancer cells. Three days after plating, cells were exposed for 10 days to the indicated concentrations of compounds in the presence or absence of 0.1 nMEg. Media were changed at 2- or 3-day intervals. At the end of the incubation period, cell number was determined by measurement of DNA content. Data are expressed as the means SEM of triplicate dishes. When the SEM overlaps with the symbol used, only the symbol is illustrated (Simard et at., 1997a).

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