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PubMed1995

Synergistic interaction between cisplatin and tamoxifen delays the emergence of cisplatin resistance in head and neck cancer cell lines.

The interaction between cisplatin (cDDP) and tamoxifen (TAM) was evaluated in the human head and neck squamous-carcinoma cell lines UM-SCC-10B and UM-SCC-5. Synergy between cDDP and TAM was demonstrated in the UM-SCC-10B cell line. Concordant with the synergistic effect between cDDP and TAM, the rate of development of resistance to cDDP was delayed when selections were performed in the presence of TAM. However, in the UM-SCC-5 cell line, TAM was neither synergistic nor did it delay the development of cDDP resistance. The difference with respect to the synergistic interaction of cDDP with TAM and the effect on the development of cDDP resistance in the UM-SCC-10B and UM-SCC-5 cell lines was not related to any significant difference in the accumulation of the cDDP analog [3H]-cis-dichloro(ethylenediamine)platinum(II) (DEP), drug sensitivity [concentrations inhibiting colony formation by 50% (IC50 values) were 6.5 and 7.2 microM for cDDP and 3.5 and 3.2 microM for TAM, respectively], the number of estrogen and progesterone receptors (negative in both cell lines), the number of antiestrogen binding sites (404 +/- 85 and 353 +/- 24 fmol/mg protein, respectively), or the affinity of TAM for these binding sites (1.7 and 1.5 nM, respectively). Importantly, however, we demonstrated that TAM can delay the emergence of resistance to cDDP in head and neck carcinomas and that this effect is linked to the nature of the interaction between cDDP and TAM.

Binding Sites↗
PubMed1989

Autoradiographic localization of [3H]hydroxytamoxifen to uterine oestrogen- and antioestrogen-binding sites.

Immature rats were injected subcutaneously with 0.36 micrograms of [3H]hydroxytamoxifen ([3H]TAM(OH)) or 0.24 microgram of [3H]oestradiol in oil, and 4 h later uteri were processed for thaw-mount autoradiography. The specificity of [3H]TAM(OH) localization was determined by injecting a 200-fold excess of unlabelled TAM(OH) or a 20-, 200- or 2000-fold excess of oestradiol 1 h before injection of [3H]TAM(OH). After injection of [3H]TAM(OH) or [3H]oestradiol, autoradiograms showed concentration of radioactivity in nuclei of stromal, epithelial and myometrial cells, but this labelling varied among the cell types depending upon which compound was injected. After [3H]TAM(OH) injection, the decreasing order of labelling intensity was stroma, myometrium, epithelium; after [3H]oestradiol injection the decreasing order was stroma, epithelium, myometrium. Injection of TAM(OH) before [3H]TAM(OH) eliminated nuclear labelling in all the uterine cell types. Injection of oestradiol before [3H]TAM(OH) decreased nuclear labelling and resulted in the concentration of label in the cytoplasm of luminal epithelium which was not present when [3H]TAM(OH) was injected alone. Cytoplasmic labelling increased initially as the oestradiol competition dose increased, but the increase in labelling did not continue with increasing concentrations of oestradiol. The results indicate that antioestrogen and oestrogen localize to nuclei of the same uterine cell types, but that cellular uptake differs among the tissue compartments. The results also suggest that a high concentration of antioestrogen-binding sites exist in the cytoplasm of the uterine luminal epithelium.

Animals↗
PubMed1999

Comparison of the synergistic effects of tamsulosin versus phentolamine on penile erection: in vitro and in vivo studies.

In vitro and in vivo studies were performed to determine the potential use of tamsulosin (TAM) versus phentolamine (PHE) for intracavernosal injection (ICI) therapy when mixed with papaverine (PAP) and/or prostagladin E1 (PGE1) or with vasoactive intestinal polypeptide (VIP) for the treatment of erectile dysfunction. We performed isometric tension studies on rabbit (n = 15), dog (n = 5), and human (n = 10) cavernous smooth muscle strips with TAM, PAP, PHE, VIP, PGE1, and the combinations of PAP and PHE; PAP and TAM; VIP and PHE; VIP and TAM; PAP, PGE1 and PHE; and PAP, PGE1 and TAM. TAM-containing trimix (PAP 18.75 mg, PGE1 6.25 micromg, and TAM 0.875 mg per ml) or PHE-containing trimix (PAP, PGE1, and PHE 0.625 mg per ml) were also injected into the cavernous bodies of ten mongrel dogs. Among the single agents, TAM and PGE1 (only in human) had the strongest effect on the relaxation of cavernous muscles in rabbit, dog, and human strips (P<0.05). Relaxation responses to 2- or 3-drug mixtures containing tamsulosin were also significantly better (P<0.05) than PHE-containing ones in rabbit, dog, and human strips. The increase in intracavernosal pressure with a TAM-containing trimix was higher than with a PHE-containing one (0.03 ml; 81.2 vs. 75.8 mm Hg, 0.04 ml; 103.2 vs. 94.3 mm Hg), although not statistically different. The drop in systemic blood pressure was lower after injection of a TAM-containing trimix than a PHE-containing one, although not statistically different. In conclusion, tamsulosin might be a more efficacious and safer agent to use for ICI therapy than phentolamine.

Adrenergic alpha-Antagonists↗
PubMed2003

Tamoxifen induces apoptosis in Fas+ tumor cells by upregulating the expression of Fas ligand.

PURPOSE: Tamoxifen (TAM), a nonsteroidal anticancer agent, is used in the treatment of breast cancer. In the current study, we investigated whether TAM induces apoptosis in tumor cells by altering the expression of Fas and Fas ligand (FasL). METHODS: Several tumor cell lines were used to test the ability of TAM to induce apoptosis, which was studied using the TUNEL assay. The effect of TAM on the expression of Fas and FasL was analyzed using a flow cytometer. RESULTS: TAM was found to suppress the growth of an estrogen receptor-positive human mammary tumor cell line (T-47D) by inducing apoptosis. Interestingly, TAM also induced apoptosis in an estrogen receptor-negative murine T cell lymphoma cell line, EL-4. The ability of TAM to induce apoptosis in T-47D and EL-4 tumor cells correlated with the increased expression of FasL but not Fas on the tumor cells. Similar to TAM, a metalloproteinase (MP) inhibitor, which is known to increase the expression of membrane-bound FasL, was found to induce apoptosis in both T-47D and EL-4 tumor cells by increasing the expression of FasL but not Fas. Furthermore, both TAM and the MP inhibitor failed to induce apoptosis in L1210 tumor cell lines that failed to express FasL. CONCLUSIONS: The current study demonstrates that TAM can induce apoptosis in Fas(+) tumor cells by upregulating FasL.

Animals↗
PubMedDate not supplied

[125I]iododesethyl tamoxifen aziridine: synthesis and covalent labeling of the estrogen receptor with an iodine-labeled affinity label.

Iododesethyl tamoxifen aziridine (I-Tam-Az), an analog of the estrogen receptor-affinity label tamoxifen aziridine (Tam-Az) in which the ethyl group has been replaced by an iodine, has been prepared by two routes: (a) metallation of a bromotriarylethylene system, followed by reaction with iodine, and aziridinylation, and (b) direct iodination of a trimethylstannyl triarylethylene system that is the immediate precursor of I-Tam-Az. The latter method can be used to prepare [125I]I-Tam-Az rapidly and in good yield, both at carrier-added and no-carrier-added levels; specific activities greater than 200 Ci/mmol have been obtained. In competitive radiometric binding assays with the estrogen receptor, I-Tam-Az has an apparent affinity of ca. 20%, equivalent to that of Tam-Az. It also undergoes rapid and selective time-dependent, irreversible binding to the estrogen receptor. [125I]I-Tam-Az reacts covalently with estrogen receptor in uterine cytosol preparations; its attachment is rapid and efficient, but somewhat less selective than that of Tam-Az. Estrogen receptor in intact MCF-7 human breast cancer cells can also be labeled with [125I]I-Tam-Az, and autoradiographic analysis of salt extracts of labeled nuclear estrogen receptor on SDS-polyacrylamide slab gels shows highly selective labeling of a 65K protein. [125I]I-Tam-Az is an efficient, selective affinity label for the estrogen receptor, available at high specific activity, and should be useful in studies on estrogen receptor structure, dynamics, and chromatin interactions.

Affinity Labels↗
PubMed1993

Characteristics of a membrane-associated antilactogen binding site for tamoxifen.

The antilactogen binding site (ALBS) is a membrane associated protein to which tamoxifen (TAM) and related non-steroidal antiestrogens, but not estrogen, bind. It is through this site that TAM inhibits lactogen binding to the prolactin (Prl) receptor and subsequent Prl induced growth and differentiation in target tissues. Binding of lactogens to the Prl receptor is inhibited by TAM or 4-hydroxy-TAM at 4 degrees C as well as room temperature, thus suggesting that the ALBS is not an enzyme. TAM acts by inhibiting the binding of lactogens to the receptor rather than promoting dissociation of the hormone-receptor complex. Lactogens bind to mammary gland membranes with an Kd of 4.3-8.2 x 10(-10) M. In the presence of 10(-7) M TAM the affinity decreased to a Kd of 0.8-1.6 x 10(-9) M. Binding of 3H-TAM to mammary gland membranes was effectively inhibited by an anti-Prl receptor antibody, thus suggesting a close relationship between the Prl receptor and the ALBS. Separate affinity purification of the ALBS and the Prl receptor resulted in peak fractions demonstrating specific binding activity for both TAM and lactogenic hormones. Re-isolation of the affinity purified Prl receptor on a TAM-Sepharose affinity resin again resulted in co-elution of both binding activities. The isolates from both affinity resins contained primarily a single band with an apparent molecular mass of 90 kDa. This band was precipitated with the anti-Prl receptor antibody and specifically bound the affinity label ring-3H-TAM aziridine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Tamoxifen induces the expression of maspin through estrogen receptor-alpha.

Maspin (mammary serine protease inhibitor) is a tumor suppressor gene that plays an important role in inhibiting tumor growth, invasion and metastasis. Maspin expression is down regulated at transcription level in primary and metastatic breast tumor cells. Previous studies on hormonal regulation of maspin prompt us to test whether an estrogen antagonist tamoxifen (TAM) can exert its anti-tumor function by up regulating maspin gene expression. For this purpose, we first tested whether maspin promoter could be activated in normal and several breast tumor cells. We then carried out a series of promoter analysis in which estrogen receptors and TAM were reconstituted in an in vitro cell culture system. Here we report our new finding that tumor suppresser gene maspin is one of the TAM target genes. TAM induces a maspin/luciferase reporter in cell culture and this induction requires the presence of (estrogen receptor alpha) ERalpha but not estrogen receptor-beta (ERbeta). Maspin promoter deletion and mutation analysis showed that the cis element(s) within a region between -90and+87 bp but not the HRE site (-272 bp) was involved in TAM induction of maspin expression. TAM bound ERalpha may directly control maspin gene expression through the interaction with cofactor (s). Analysis using several ERalpha mutants showed that the N-terminal A/B motif (AF-1) was critical for maspin basal level transcription activation. An ERalpha mutant with point mutations at DNA binding domain abolished estrogen induction of an ERE-luciferase reporter but was still active in activating maspin promoter by TAM. LBD-AF2 domain was required for ERalpha-dependent TAM induction. Deletion of LBD-AF2 or a point mutation in the ERalpha LBD-AF2 region (LBDmtL539A) completely abolished the activation of maspin promoter, suggesting that TAM induction of maspin involves the recruitment of cofactor(s) by ERalpha to the maspin promoter region. This finding indicates that one of the pathways for cancer prevention and tumor inhibition by TAM is mediated through the activation of tumor suppressor gene maspin in breast cancer.

Animals↗
PubMed2003

Involvement of PKA and Sp1 in the induction of p27(Kip1) by tamoxifen.

We have previously shown that tamoxifen (Tam) inhibits proliferation of estrogen receptor-negative human non-small cell lung cancer cells and this inhibition is associated with induction of p27(Kip1). In this study, we investigated the mechanism by which Tam increases p27(Kip1) expression. Because intracellular p27(Kip1) protein level is mainly controlled via posttranslational regulation, we first tested whether Tam might affect protein stability of p27(Kip1). Metabolic labeling and pulse chase assays showed that Tam did not affect the half-life of this protein. We next examined whether Tam enhanced p27(Kip1) expression through transcriptional activation. Our results demonstrated that Tam directly stimulated the p27(Kip1) promoter in lung cancer cells. Deletion and mutation analysis revealed that two Sp1 consensus sites located between -545 and -532bp from the transcription start site were crucial for the induction of p27(Kip1) by Tam. Conversely, mutation in a CTF site (-525/-520) nearby these two Sp1 sites had little effect. Electromobility shift assays showed that Sp1 transcription factor bound to these consensus sites and the DNA binding activity of Sp1 was enhanced by Tam. Our data also demonstrated that induction of p27(Kip1) by Tam was inhibited by protein kinase A inhibitor H89, but not by protein kinase C inhibitor calphostin C and mitogen-activated kinase kinase inhibitor PD98059. Taken together, our results suggest that Tam transcriptionally activates p27(Kip1) expression via the Sp1 consensus sites in the p27(Kip1) promoter and PKA is involved in this process.

Antineoplastic Agents, Hormonal↗
PubMed1996

Regulation of gene expression of various phase I and phase II drug-metabolizing enzymes by tamoxifen in rat liver.

The objective of the present investigation was to evaluate the effect of tamoxifen (TAM) on the gene expression of different phase I and phase II drug-metabolizing enzymes. Groups of male and female F344/NCr rats were administered either corn oil or TAM (2.8 to 45 mg/kg body wt x 14 days) dissolved in corn oil by gavage. An additional group of rats received a diet supplemented with phenobarbital (PB, 500 ppm). Northern blot analyses of total liver RNA were conducted using [32P]-labeled cDNA or oligonucleotide probes coding for different sulfotransferase (ST); UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), epoxide hydrolase (EPH) or cytochrome P450 (CYP) mRNA transcripts. In male rats, TAM increased the levels of STel, STa and STpl mRNAs, whereas PB increased only the STel mRNA. In female rats, there was no expression of STel and STHA mRNA in either control or TAM-treated animals. TAM and PB increased UGTBe/p mRNAs in all rats, whereas UGTml mRNA was elevated only in PB-treated animals. EPH mRNA was elevated markedly in all rats treated with TAM and PB, whereas GSTya/ye mRNA was highly increased by PB, but only marginally increased by TAM. Finally, TAM increased CYP3A1 mRNA, and slightly increased CYP2B1 mRNA, whereas PB highly elevated mRNAs for both of these CYP genes. In conclusion, treatments of rats with TAM increased the mRNA levels of many phase I and phase II drug-metabolizing enzymes, and this pleiotypic response to TAM seems to be different from other prototype inducers such as PB or dioxin (TCDD).

Animals↗
PubMed1998

Tamoxifen modulation of carboplatin cytotoxicity in a human U-138 glioma cell line.

Glioma cells express high protein kinase C (PKC) activity, which may represent an important therapeutic target. Tamoxifen (TAM) has moderate PKC-inhibiting activity, blocking DNA synthesis and cellular proliferation in human glioma cells at concentrations that can be achieved therapeutically. Carboplatin (CBDCA), a second-generation platinum derivative, induces intra- and interstrand DNA-protein crosslinks producing inhibition of tumor-cell growth. In the present study, the effect of TAM, CBDCA, and the combination of both was evaluated against the human established U-138 glioma cell line during the exponential growth phase (48-72 h) by means of both the Biorad protein assay (BPA) method and Trypan blue exclusion study (TBES). Both TAM and CBDCA reduced the cellular growth rate, with a median 50%-inhibiting concentration (IC50) of 12.5 microM for TAM and 350 microM for CBDCA. The U-138 glioma cell line showed a moderate response to 100 microM of CBDCA, with < or = 10% reduction of the growth rate. The association of both chemotherapeutic agents induced a 98% reduction of the IC50 dose of TAM (0.1 microM), and a 71% reduction of the IC50 dose of CBDCA (100 microM). During the combinational TAM CBDCA exposure we observed a cytotoxic effect of TAM at concentrations lower than 0.1 microM, not recognized using it as a single drug. The differences observed among the IC50 doses (TAM, CBDCA, TAM-CBDCA) and among treated and untreated matched control cells were statistically significant (P < 0.01). Our results confirm previous observations about the efficacy in vitro of TAM against human glioma cell lines and show a marked enhancement of this activity by CBDCA.

Antineoplastic Agents↗
PubMed1997

Determination of tamoxifen and metabolites in serum by capillary electrophoresis using a nonaqueous buffer system.

Tamoxifen (TAM), an antiestrogen, is widely used to treat hormone-dependent breast cancer in post-menopausal women. TAM may be used as a chemopreventive agent in women of child-bearing age; however, few data exist describing potential TAM-induced fetal toxicity. In support of the National Toxicology Program's characterization of reproductive and developmental effects of TAM, this work describes an analytical technique utilizing capillary electrophoresis (CE) for the detection of circulating levels of TAM, N-desmethyltamoxifen (DMT), and 4-hydroxytamoxifen (4-HT) in maternal rodent serum. Greater than 90% of 3H-labeled TAM was extractable from serum using 98:2 hexane-isoamyl alcohol. Optimum separation of TAM, DMT, and 4-HT was obtained on a 57 cmx50 microm capillary using a nonaqueous buffer system of 1:1 methanol-acetonitrile containing 50 mM ammonium acetate and 1% acetic acid. 4-Dimethylaminopyridine was used as internal standard. Temperature and voltage were optimized at 40 degrees C and 15 kV, respectively. The limit of detection of TAM by UV detection at 214 nm was approximately 800 amol. TAM and DMT were confirmed in serum of female rats 4 h following a single oral dose of 120 mg/kg. Transplacental exposure of TAM to fetal tissue will be evaluated using this technique.

Animals↗
PubMed2003

Addition of adjuvant tamoxifen to cyclophosphamide, methotrexate and 5-fluorouracil for premenopausal women with oestrogen receptor-positive breast cancer.

OBJECTIVE: To study the value of adjuvant tamoxifen (TAM) in premenopausal women with oestrogen receptor (ER)-positive breast cancer who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) polychemotherapy. METHODS: Four hundred and two premenopausal ER-positive breast cancer patients who received CMF chemotherapy between January 1990 and December 1999 were retrospectively studied. Disease-free survival (DFS) and overall survival (OS) were used to evaluate the clinical value of TAM therapy. The relationships between nodal status and TAM were also analysed. RESULTS: After a mean of 41 months of follow-up, 43 (13.7%) patients died of breast cancer and 68 (19.9%) patients suffered recurrence. There was a significant difference between TAM and non-TAM treatment groups for DFS (p=0.0058), but no significant difference for OS. For node-negative patients, there was no significant difference between the TAM and non-TAM treatment groups for either DFS or OS. For node-positive patients, the difference between TAM and non-TAM treatment groups was significant for both DFS and OS (p=0.0497 and p=0.0285, respectively). CONCLUSION: TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.

Adult↗
PubMed1997

Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model.

The purpose of this study was to compare the effects of droloxifene (DRO), tamoxifen (TAM), and 17 alpha-ethynyl estradiol (EE) on bone mineral density, bone histomorphometry, total serum cholesterol, and uterine histology in the ovariectomized (ovx) rat model. Sprague-Dawley female rats at five months of age were sham-operated and treated orally with vehicle (n = 8), or ovx (n = 56) and treated (p.o.) with either vehicle, DRO at 0.1 or 1.0 mg/kg daily, TAM at 0.1 or 1 mg/kg daily, or EE at 3 or 30 micrograms/kg daily for 4 weeks. The uterine wet weight and uterine histologic parameters (cross-sectional tissue area, stromal thickness, and luminal epithelial thickness) were determined. Femoral and lumbar vertebral bone mineral density was determined ex vivo using dual energy x-ray absorptiometry. Static and dynamic cancellous bone histomorphometry was performed on double-labeled, undecalcified longitudinal sections from proximal tibial metaphyses. Furthermore, the changes in total serum cholesterol and body weight gain were also determined. Compared to sham controls, ovx for four weeks significantly decreased uterine weight (-72%), uterine cross-sectional tissue area (-74%), stromal thickness (-52%), and luminal epithelial thickness (-53%). ovx rats treated with EE at 30 micrograms/kg/day maintained these parameters at the levels of sham controls. Uterine weight and uterine cross-sectional tissue area in 3 micrograms/kg/day of EE treated ovx rats were higher than that of vehicle-treated ovx rats. In ovx rats treated with TAM at both 0.1 and 1 mg/kg/day, these parameters were significantly less than sham controls but significantly higher than ovx controls. DRO at 0.1 mg/kg/day had no effects on all above parameters. Uterine weight and cross-sectional tissue area in 1 mg/kg/day of DRO treated ovx rats was slightly but significantly higher than that in ovx controls. However, DRO at 1 mg/kg/day had no effects on uterine stromal thickness and luminal epithelial thickness compared to ovx controls. The ovx-induced decrease in femoral and lumbar vertebral bone mineral density was prevented by treatment with EE at 30 micrograms/kg/day, TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Similarly, the decrease in bone mass and the increase in bone resorption and bone turnover in proximal tibial metaphyses were prevented by treatment with EE at 30 micrograms/kg/day or TAM at both 0.1 and 1 mg/kg/day, or DRO at 1 mg/kg/day. Total serum cholesterol decreased significantly in ovx rats treated with either EE, DRO, or TAM at all dose levels compared to vehicle treated ovx controls (-32% to -56%). The ovx-induced body weight gain was completely prevented by EE at 30 micrograms/kg/day, and partially prevented by DRO at 1 mg/kg/day. TAM at both 0.1 and 1 mg doses caused a significant decrease in body weight compared to both sham and ovx controls. Our results indicated that DRO prevented ovx-induced bone loss and lowered total serum cholesterol with an ED50 less than 1 mg/kg/day. The bone protective and cholesterol lowering effects of DRO were comparable to those observed with TAM and EE. However, DRO differed from TAM and EE in its lack of significant estrogenic effects on uterine tissue at doses which were bone protective. These data suggest that DRO may be a significant alternative to EE and TAM for prevention and treatment of postmenopausal osteoporosis.

Absorptiometry, Photon↗
PubMed2003

Alpha-hydroxylation of tamoxifen and toremifene by human and rat cytochrome P450 3A subfamily enzymes.

An increased risk of developing endometrial cancer is observed in breast cancer patients treated with tamoxifen (TAM) and in healthy women undergoing TAM chemoprevention therapy. TAM-DNA adducts were detected in the endometrium of women taking TAM (Shibutani, S., et al. (2000) Carcinogenesis 21, 1461-1467) and are formed primarily through O-sulfonation of alpha-hydroxytamoxifen (alpha-OHTAM). To explore the genotoxicic mechanisms of TAM, TAM was incubated with one of multiple human cytochrome P450 enzymes, i.e., P450 1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, 3A7, 4A11, 4F2, 4F3A, or 4F3B, in a NADPH regenerating system, and the metabolites were identified using HPLC/UV analysis with authentic standards. Among the 18 human P450 enzymes, P450 3A4 generated a significant amount of alpha-OHTAM. When some rat P450 enzymes were examined, P450 3A2 also catalyzed alpha-hydroxylation of TAM. Similarly, human P450 3A4 and rat P450 3A1 and 3A2 converted toremifene (TOR, a chlorinated TAM analogue) to alpha-hydroxytoremifene (alpha-OHTOR). The formation of alpha-OHTAM and alpha-OHTOR by these P450 enzymes was confirmed by tandem mass spectroscopy. Only the P450 3A subfamily enzymes are able to alpha-hydroxylate TAM and TOR. Although the formation of alpha-OHTOR by these enzymes was much higher than that of alpha-OHTAM, TOR is known to be much less genotoxic than TAM. The results support our proposed mechanism that the lower genotoxicity of TOR is due to limited O-sulfonation of alpha-OHTOR by hydroxysteroid sulfotransferases, resulting in the poor formation of DNA adducts (Shibutani, S., et al. (2001) Cancer Res. 61, 3925-3931).

Animals↗
PubMed1997

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study.

The study was planned to compare, in a prospective double-blind randomized trial, the efficacy and safety of toremifene (TOR) and tamoxifen (TAM) in post-menopausal patients with advanced breast cancer who have not had prior systemic therapy for advanced disease. Four hundred and fifteen post-menopausal patients with oestrogen receptor (ER)-positive or ER-unknown advanced breast cancer were randomly assigned to receive daily either 60 mg TOR or 40 mg TAM. The patients were stratified to measurable and non-measurable but evaluable groups. They were assessed for response to therapy, time to progression (TTP), time to treatment failure (TTF), response duration, overall survival and drug toxicity. Two hundred and fourteen patients were randomized into TOR and 201 into TAM treatment. The response rate (complete + partial) was 31.3% for TOR and 37.3% for TAM (P = 0.215). The 95% confidence interval (CI) for the 6% difference was -15.1% to 3.1%. The median TTP was 7.3 months for TOR and 10.2 months for TAM (P = 0.047). The 95% CI for the hazard ratio of 0.80 was 0.64-1.00. A percentage of the TOR patients (9.8%) and the TAM patients (18.9%) discontinued the treatment prematurely (P = 0.011) for various reasons. Consequently, the median TTF of 6.3 vs 8.5 months did not differ significantly (P = 0.271). The hazard ratio was 0.89 and the subsequent 95% CI 0.73-1.09. The median overall survival was 33.0 months for TOR and 38.7 months for TAM (P = 0.645). The hazard ratio was 0.94 with 95% CI of 0.73-1.22. The transient difference in TTP may be related to an imbalance in ER content of the tumours. When only patients with ER-positive tumours were considered (n = 238), no difference between two treatments was seen (P = 0.578). TAM was associated with an overall slightly higher frequency of adverse drug reactions than TOR (44.3 vs 39.3%) and a higher discontinuation rate due to these events (3.5% vs 0.9%). Treatment-emerged moderate dizziness (P = 0.026) and cataracts (P = 0.026) were more frequent among TAM than among TOR patients. In conclusion, TOR (60 mg day(-1)) and TAM (40 mg day(-1)) are equally effective and safe in the treatment of advanced post-menopausal ER-positive or ER-unknown breast cancer.

Adult↗
PubMed2005

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene.

The putative presence of a mutation in codon 12 of the K-ras gene was investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated breast cancer patients. DNA was extracted from fresh cytologic samples of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients. Mutations were detected by enriched PCR and an enzyme-linked mini-sequence assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples, and in only one TOR-treated endometrium (P<0.003). In 24 premenopausal patients, K-ras mutation was found in seven (43.8%) of 16 patients with less than 47 months of TAM treatment, while none was found in eight patients with more than 48 months of TAM treatment (P<0.03). In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in three (15.8%) of 19 patients with less than 23 months of TAM treatment, while it was found in 16 (61.5%) of 26 patients with 24-47 months of TAM treatment and nine (52.9%) of 17 patients with more than 48 months of TAM treatment (P=0.002). The presence of K-ras mutation is significantly influenced by the duration of TAM treatment and menstrual status of the patients. TOR may have a lower potential genotoxicity than TAM.

Adult↗
PubMed1983

Physicochemical and genetic evidence for specific antiestrogen binding sites.

In rat uterus and human breast cancer MCF-7 cell cytosol, the antiestrogens tamoxifen (Tam) and 4-hydroxytamoxifen (OH-Tam) bind to "antiestrogen binding sites" (ABS), which do not bind estradiol (E). Demonstrated in total cytosol by binding studies with radioactive antiestrogens in the presence of a large concentration of E, ABS can be physically separated from E-binding estrogen receptor (ER) by removing the latter with an E-containing bioaffinity adsorbent or with heparin-Sepharose gel. ABS concentration is 10-20% of that of ER; the Kd for Tam and OH-Tam is 1-2 x 10(-9) M, whereas the Kd of OH-Tam binding by ER (approximately equal to 1 x 10(-10) M) is approximately equal to 1/50 that of Tam. Other triphenylethylene antiestrogens compete against Tam for binding to ABS, contrary to steroid hormones. Sucrose gradient ultracentrifugation analyses of total cytosol and of affinity gel effluents show a heterogenous pattern of ABS from 10 to 40 S, unchanged by 0.4 M KCl and limited trypsinization (which however provoke transitions of ER from 8S to 4S forms) and by 20 mM molybdate (which stabilizes the 8S form of ER and prevents large aggregates). Preliminary results suggest that ABS may be associated with particulate components of the cell. RTx6 cells of a clone selected from MCF-7 cells for resistance to the antigrowth effect of Tam have ER in the same concentration and have similar affinity for E and antiestrogens as do unselected MCF-7 cells. However, RTx6 cells have virtually no ABS detectable by binding and gradient ultracentrifugation studies. It is proposed that the double binding of Tam and OH-Tam to ER and ABS in estrogen target cells may be related to the complex double series of estrogenic and "antiestrogenic" activities displayed by nonsteroidal triphenylethylene derivatives.

Animals↗
PubMed1996

Activation of 4-hydroxytamoxifen and the tamoxifen derivative metabolite E by uterine peroxidase to form DNA adducts: comparison with DNA adducts formed in the uterus of Sprague-Dawley rats treated with tamoxifen.

Daily intraperitoneal treatment of female Sprague-Dawley rats with either 5, 10 or 20 mg/kg tamoxifen (TAM) for 1 week increased the level of peroxidase activity in the uterus 2- to 10-fold compared to the control level. Using uterine extracts prepared from control and TAM treated animals, we investigated the activation of 4-hydroxytamoxifen (4-HO-TAM) and (E,Z)-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene (cis/trans-metabolite E) to form DNA adducts. Activation of 4-HO-TAM by uterine extracts prepared from either control or TAM-treated rats produced one major (a) and two minor DNA (b and c) adducts. A similar activation of cis/trans-metabolite E produced two adducts (d and e). There was good correlation between levels of uterine peroxidase activity and levels of DNA adducts formed by 4-HO-TAM and cis/trans-metabolite E. Activation of 4-HO-TAM and cis/trans-metabolite E with horseradish peroxidase (HRP) produced the same adducts as observed by activation with uterine extract. Treatment of Sprague-Dawley rats with 5 and 10 mg/kg for 7 days produced eleven DNA adducts in the liver with no adducts detected in the uterus. However, treatment of rats with 20 mg/kg of TAM for 7 days produced the same adduct pattern in the liver and also one major adduct (1) in the uterus with a relative adduct level of 6.4 - 4.1 x 10(-9). Tamoxifen-DNA adduct 1 detected both in the liver and in the uterus of treated rats was similar to adducts produced by activation of 4-HO-TAM with either uterine extract or HRP. The results of these studies suggest a general model whereby the tamoxifen metabolite 4-HO-TAM is further activated in the uterus by peroxidase enzymes to form DNA adducts.

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