A Tamoxifen

It has been suggested that tamoxifen, one of the most effective therapeutic and chemopreventive agent for breast cancer, modulates protein kinase C through oxidative stress in breast cancer cells [194], Unfortunately, most breast cancers initially responsive to tamoxifen treatment later become resistant. Schiff et al. [195] suggested that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and depends on significantly enhanced SOD activity in tumors. 

Gottardis MM, Ricchio ME, Satyaswaroop PG, Jordan VC (1990) Effect of steroidal and nonsteroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCalOl) in athymic mice. Cancer Res 50 3189-3192... 

Toremifen is a SERM considered a tamoxifen analog characterized by one chlorine atom and is approved for first-line treatment of metastasic breast cancer in postmenopausal women who have tumors that are either ER(+) or of unknown status. In a 3-year face-to-face study with tamoxifen, there were no significant differences between both drugs. The number and profile of adverse events are also similar. Experience with toremifen is limited and far from that accumulated with tamoxifen. 

Species Differences. Species differences in metabolism are amongst the principal reasons that there are species differences in toxicity. Differences in cytochrome P450 is one of the most common reasons for differences in metabolism. For example, Monostory et al. (1997) recently published a paper comparing the metabolism of panomifene (a tamoxifen analog) in four different species. These data serve to address that the rates of metabolism in the non-human species was most rapid in the dog and slowest in the mouse. Thus, one should not a priori make any assumptions about which species will have the more rapid metabolism. Of the seven metabolites, only one was produced in all four species. Both the rat and the dog produced the two metabolites (M5 and M6) produced by human microsomes. So how does one decide which species best represents humans One needs to consider the chemical structure of the metabolites and the rates at which they are produced. In this particular case, M5 and M6 were relatively minor metabolites in the dog, which produced three other metabolites in larger proportion. The rat produced the same metabolites at a higher proportion, with fewer other metabolites than the dog. Thus, in this particular instance, the rat, rather than the dog, was a better model. Table 18.8 offers a comparison of excretion patterns between three species for a simple inorganic compound. 

Tamoxifen has several adverse effects on the skin, including edema, flushing, rashes, hyperhidrosis, urticaria, alopecia, and hypertrichosis. Radiation recall dermatitis, a severe painful inflammatory skin reaction in sites that have previously been exposed to ionized radiation, can occur in patients taking tamoxifen (59). In one case the tamoxifen was withdrawn and the skin healed spontaneously in 7 weeks (60). Toremifene, a tamoxifen analogue, was well tolerated during 18 months of continuous treatment no signs of radiation recall developed. 

Puglisi F, Aprile G, Sobrero A. Tamoxifen-induced total alopecia. Ann Intern Med 2001 134(12) 1154-5. 

Hayashi, S. and McMahon, A. P. (2002) Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre a tool for temporally regulated gene activa-tion/inactivation in the mouse. Dev Biol244, 305-318. 

Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K., and MacMahon, A.P. (1998) Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8, 1323-1326. 

Figure 8.4 Chemical structures (a) tamoxifen (b) butylated hydroxytoluene (c) atrazine.

Glatt, H Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S. and Phillips, D.H. (1998) Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis, 19, 1709-1713. 

Catherino, W.H., Wolf, D.M. and Jordan, V.C. (1995) A naturally occurring estrogen receptor mutation results in increased estrogenicity of a tamoxifen analog. Molecular Endocrinology, 9, 1053-1063. 

Mouriquand, J., Genevey, M. C., Beriel, H., Payan, R., and Mermet, M. A., Tamoxifen-induced fluorescence as a predictive test for hormone responsiveness of breast carcinoma. Dev. Oncol. 49, 221-230 (1986). 

Nawata, H., Bronzert, D., and Lippman, M. E., Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J. Biol. Chem. 256,5061-5021 (1981). 

First reported in the 1970s, tamoxifen was the first synthetic NR small molecule to show differential tissue effects. The primary reason it has not been widely used to treat menopausal symptoms is the fact that this molecule shows stimulatory effects on the uterus, which cause a significant risk for endometrial cancer [86]. However, tamoxifen remains a first-line treatment for ER-positive breast cancer. A second generation SERM, raloxifene, was originally developed as a tamoxifen follow-up for breast cancer, but it was demonstrated that this molecule has significant osteoporosis protective effects without the endometrial activities relative to tamoxifen [87]. The molecular basis for these ER-modulating activities has been the focal point for a wide body of pharmacological research [88], One proposed mechanism is the differential effects of SERM-bound ER to promote corepressor association versus coactivator association [89, 90]. 

FIGURE 7.6 (a) Tamoxifen, (b) 4-Hydroxytamoxifen inside the estrogen receptor (structure was drawn using 3ERT.pdb). 

Farabegoli F, Papi A, Bartolini G, Ostan R, Orlandi M (2010) (-)-Epigallocatechin-3-gallate downregulates Pg-P and BCRP in a tamoxifen resistant MCF-7 cell line. Phytomedicine 17 356-362... 

Renal disease Tamoxifen has been found to be safe and effective in patients with normal renal function, but until recently there was no evidence regarding its safety or otherwise in women with impaired renal function. A study in 29 patients in whom impaired renal function ranged from mild to severe has suggested that a tamoxifen... 

Rousset-Jablonski C, Thalabard J-C, Gompel A. Tamoxifen contraindicated in women with hereditary angioedema Ann Oncol 2009 20 1281-2. 

Florian, J. A., J. L. Eiseman, and R. S. Parker. Nonlinear Model Predictive Control for Dosing Daily Anticancer Agents A Tamoxifen Treatment of Breast Cancer Case Study, Comput. Biol. Med., 38, 339 (2008). 

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