Tamoxifen hydroxytamoxifen

Recently, Jaouen and coworkers discovered that an organometaiiic derivative of the known breast cancer drug. Tamoxifen (hydroxytamoxifen, a liver metabolite, is the active drug), Ferrodfen, 3, and its derivatives, were potential candidates for... 

Marques, M. M. Beland, F. A. Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide. Carcinogenesis 1997, 18, 1949-1954. 

A relatively stable QM is produced by initial P450-catalyzed aromatic hydroxylation of the SERM tamoxifen to yield 4-hydroxytamoxifen, followed by a cytochrome P450-catalyzed direct two-electron oxidation (Scheme 10.9).7 58 This QM is extremely long lived at physiological pH and temperature (tl/2 3 h, Table 10.2),59 most likely... 

Custodio JB, Almeida LM, Madeira VM (1993) The active metabolite hydroxytamoxifen of the anticancer drug tamoxifen induces structural changes in membranes. Biochim Biophys Acta 1153(2) 308-314... 

Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M (1991) Acquired tamoxifen resistance correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83 1477-1482... 

Both unsymmetrical diols and alkenes can be prepared by applying these methods to mixtures of two different carbonyl compounds. An excess of one component can be used to achieve a high conversion of the more valuable reactant. A mixed reductive deoxygenation using TiCl4/Zn has been used to prepare 4-hydroxytamoxifen, the active antiestrogenic metabolite of tamoxifen. 

Wiseman H, Cannon M, Arnstein HRV, Halliwell B. Mechanism of inhibition of lipid peroxidation by tamoxifen and 4-hydroxytamoxifen introduced into liposomes. Similarity to cholesterol... 

The mouse has less sulfotransferase activity with respect to the a-hydroxytamoxifen, but more glucuronosyl transferase activity. The resulting glucuronic acid conjugation is a clear detoxication pathway, as a stable metabolite is formed, which can be readily eliminated. Hence, the mouse is much less susceptible, and although some tamoxifen is covalently bound to liver DNA, no hepatic tumors have been detected. 

Boocock DJ, Maggs JL, Brown K, et al. Major interspecies differences in the rates of O-suIphonation and O-glucuronylation of a-hydroxytamoxifen in vitro a metabolic disparity protecting human liver from the formation of tamoxifen DNA adducts. Carcinogenesis 2000 21 1851-1858. 

Crewe HK et al (2002) Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes formation of the 4-hydroxy, 4 -hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 30 869-874... 

Sun D et al (2006) Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Res 8 R50... 

IusufD et al (2011) P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J Pharmacol ExpTher 337 710-717... 

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. 

To assess the percentage of MCF-7 cells that progressed through the S-phase of the cycle during incubation with EM-652, EM-800, or tamoxifen in the presence or absence of E2, the continous BrdUrd exposure technique was used. As measured after a 48-hour exposure to BrdUrd, 72-hour pretreatment with 1 nM EM-652, EM-800, or hydroxytamoxifen alone decreased the percentage of BrdUrd-positive cells from 43.6% to 20.2%, 21.5%, and 30.9%, respectively (p<. 01) (Fig. 22A). On the other... 

Fig. 22. Effect of increasing concentrations of EM-652, EM-800, hydroxytamoxifen (OH-TAM) or tamoxifen (TAM) on the proportion of cycling MCF-7 cells after exposure to BrdUrd. Three days after plating at an initial density of 0.85 x 105 per 10-cm2 well, cells were pretreated for 3 days with the indicated concentrations of compounds in the presence (B) or absence (A) of 0.1 nME2 before changing to fresh medium containing the same compounds and 10 pM BrdUrd. Cells were then harvested after 2 days, fixed, and stained with the dye Hoechst 33358. The percentage of BrdUrd-positive cells was calculated as described by Simard et al, (1997a). Data obtained with control medium alone in the presence or absence of 0.1 nME2 are indicated on the Y axis. Data are expressed as described in the legend of Fig. 20 (Simard et al., 1997a).

This study also shows that EM-652 and EM-800 decrease the proportion of MCF-7 cells that advance through the S phase, and completely block the stimulatory effect of E2 on this parameter. In fact, EM-652 and EM-800 were at least 1000-fold more effective than tamoxifen in reducing the proportion of BrdUrd-positive cells in the presence or absence of E2, and EM-652 was six times as potent as hydroxytamoxifen in the presence of E2. 

The stimulatory effect of tamoxifen or hydroxytamoxifen on human breast cancer cell growth has been reported previously by many laboratories under in vitro (Berthois et al., 1986 Cormier and Jordan, 1989 Darbre et al, 1984 DeFriend et al., 1994a Katzenellenbogen et al., 1987 Nomura et al., 1990 Osborne et al., 1985 Poulin et... 

Fig. 3.45 Effect of drug concentration on the partition coefficients of tamoxifen (open symbols) and 4-hydroxytamoxifen (closed symbols) in DMPC bilayers (A) and in liposomes of sarcoplasmic reticulum lipids and native membranes (B). Note that the linear correlation between Kp and drug concentration is...

Fig. 3.46 Partition coefficients oflOpM tamoxifen (O) and 4-hydroxytamoxifen ( ) in DM PC bilayers as a function of temperature. Maximal partitioning is observed at main phase transition temperatures. (Reprinted from Fig. 3 of ref. 147] with permission from Academic Press.)...

The example of the anticancer dmgs tamoxifen and 4-hydroxytamoxifen shows that merely the absence or presence of certain substituents can change the distribu-... 

A similar difference has been observed for Kp M values of the anticancer drags tamoxifen and 4-hydroxytamoxifen determined in mitochondria, sarcoplasmic reticulum, and in liposomes made from lipids extracted from the corresponding native membranes [85]. The largest Kp M was observed in mitochondria, followed by sarcoplasmic reticulum and liposomes. The authors introduced for these experiments derivative spectroscopy, a reliable and rapid procedure to estimate drag partitioning into biomembranes. The method used the shift in the absorption spectra of the drug when removed from the aqueous phase to a hydrophobic environment (see Section 3.10). 

Depending on the presence or absence of the oestrogen receptor in the cells, breast cancer is often treated by endocrine therapy (tamoxifen) or chemotherapy, respectively. Organometallic derivatives of hydroxytamoxifen (e.g. ferrocifen, 16, and its... 

Keywords Anti-androgen Anti-oestrogen/Anti-oestrogenic Breast cancer Cytoto x i c/Cytotox i c i ty. Electrochemistry/Electrochemical Oestradiol Ferricenium Ferrocene Ferrocenophane Hydroxyferrocifens Hydroxytamoxifen (OH-Tam) Oestrogen receptor (ER) Oestrogen/Oestrogenic Phenol Prostate cancer Quinone Raloxifen RBA ROS Steroid Tamoxifen Testosterone Vectorisation... 

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