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PubMed2004

Prognostic relevance of tumour-associated macrophages and von Willebrand factor-positive microvessels in colorectal cancer.

Tumour-associated macrophages (TAM) are involved in tumour angiogenesis and anti-tumour immune response. In colorectal cancer (CRC), an association of high microvascular density (MVD) and unfavourable prognosis has been reported by some investigators. However, heterogeneous patient groups were studied. We, therefore, analysed the correlation between TAM and MVD and the prognostic relevance of MVD, TAM and T lymphocyte infiltration for long-term survival in a homogeneous group of 70 patients with moderately differentiated cancers of the International Union Against Cancer (UICC) stages II and III, who did not receive chemotherapy. MVD was evaluated using immunohistochemistry with antibodies against CD34 and von Willebrand factor (vWF). TAM and T lymphocytes were visualised with antibodies against CD68 and CD3, respectively. Statistical analysis did not reveal a significant correlation between TAM and T lymphocyte numbers and MVD. Multivariate analysis of immunohistochemical data from all CRC patients and the subgroup of patients with UICC stage-II CRC identified TAM- and vWF-positive microvessel numbers as prognostically relevant markers. Low numbers of TAM- and high numbers of vWF-positive microvessels were associated with an unfavourable prognosis. In conclusion, TAM- and vWF-positive microvessel numbers may serve as independent prognostic markers for patients with UICC stage-II and -III CRC and may help to identify patients with an unfavourable prognosis.

Aged↗
PubMed2006

Randomized trial of tamoxifen alone or combined with fluoxymesterone as adjuvant therapy in postmenopausal women with resected estrogen receptor positive breast cancer. North Central Cancer Treatment Group Trial 89-30-52.

PURPOSE: This clinical trial evaluated the addition of fluoxymesterone (Flu) to tamoxifen (Tam) in women with resected early stage breast cancer and attempted to corroborate the findings of superiority for the combination over Tam alone seen in a previous randomized trial in metastatic disease. PATIENTS AND METHODS: Postmenopausal women with early stage breast cancer that was known to be estrogen receptor (ER) positive were randomized to treatment with Tam (20 mg per day orally for 5 years) alone or combined with Flu (10 mg orally twice per day for 1 year). The primary endpoint was relapse-free survival (RFS) defined as local-regional or distant recurrence including ductal carcinoma in situ of the ipsilateral, but not contralateral breast, and death from any cause. RESULTS: There were 541 eligible patients entered between 1991 and 1995 and the treatment arms were balanced with respect to patient characteristics. The median follow up of patients still alive was 11.4 years. No significant difference was found between Tam plus Flu and Tam alone in terms of RFS or overall survival. The adjusted hazard ratio (Tam+Flu/Tam) for relapse or death without relapse was estimated to be 0.84 (95% CI: 0.64-1.10) and that for death was 0.89 (95% CI: 0.67-1.18). As expected there was more virilization in women who received Flu. CONCLUSIONS: This clinical trial did not demonstrate superiority of Tam plus Flu over Tam alone as adjuvant therapy for postmenopausal women with resected early breast cancer known to be ER positive.

Adult↗
PubMed2006

Tamoxifen paradoxically decreases paclitaxel deposition into cerebrospinal fluid of brain tumor patients.

BACKGROUND: P-glycoprotein (Pgp) mediates, in part, resistance to natural product chemotherapy drugs which constitute over half of the available drugs for cancer treatment. Tamoxifen (TAM) enhances intracellular deposition of natural product chemotherapy in human cell lines by inhibition of Pgp. Pgp is highly expressed in the choroid plexus and is thought to be a key component of the blood-cerebrospinal fluid barrier (BCSFB). We conducted a prospective, randomized study to assess if Pgp inhibition by TAM alters deposition of paclitaxel in cerebrospinal fluid (CSF). METHODS: Ten patients with either primary or metastatic brain tumors were randomized to: paclitaxel alone (175 mg/m2/IV) or a course of TAM (160 mg/m2 PO BID on Days 1-5) followed by paclitaxel (175 mg/m2/IV on Day 5). CSF and plasma samples were obtained following paclitaxel infusion; paclitaxel and TAM concentrations were measured by high-performance liquid chromatography assays. RESULTS: Paclitaxel was detected in the CSF of six of the 10 patients. Peak CSF paclitaxel concentrations of the paclitaxel and paclitaxel-TAM groups ranged between 3.5-57.4 and 2.3-24.6 nM, respectively. Though there was a 2.4-fold higher mean CSF paclitaxel concentration and a 3.7-fold higher median peak CSF:plasma paclitaxel ratio for those who received paclitaxel alone as compared to combined paclitaxel-TAM, it was not statistically significant (P = 0.22). In one patient enrolled to both arms, higher CSF concentrations of paclitaxel and higher paclitaxel CSF: plasma ratios were observed when given paclitaxel alone. CONCLUSIONS: The trend towards lower paclitaxel CSF concentrations when given with TAM is consistent with the published finding that Pgp's localization in the endothelial cells of the choroid plexus works in an opposite direction and keeps drugs in the CSF. Thus, agents which inhibit Pgp, such as TAM, may increase efflux of Pgp substrates out of the BCSFB and may paradoxically lower CSF concentrations of natural product chemotherapy drugs. Conceptually, this finding implies that the Pgp in the BBB and BCSFB keeps natural toxins such as paclitaxel, from entering the brain (BBB) and, if they do enter the brain, keeps them in the CSF (BCSFB) where they may be less harmful than if they re-entered the brain. Thus, our work supports this novel idea and adds to the understanding of the functions of the BCSFB.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

The anticancer drug tamoxifen induces changes in the physical properties of model and native membranes.

The interactions of tamoxifen with lipid bilayers of model and native membranes were investigated by fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene (DPH) and by intramolecular excimer formation of 1,3-di(1-pyrenyl)propane (Py(3)Py). The effects of TAM of liposomes of DMPC, DPPC and DSPC are temperature dependent. In the fluid phase, TAM reduces dynamics of the upper bilayer region as observed by Py(3)Py and has no effect on the hydrophobic region as detected by DPH. In the gel phase, the effects of TAM evaluated by Py(3)Py are not discernible for DMPC and DPPC bilayers, whereas DSPC bilayers become more fluid. However, DPH detects a strong fluidizing effect of TAM in the hydrophobic region of the above membrane systems, where DPH distributes, as compared with the small effects detected by Py(3)Py. TAM decreases the main phase transition temperature but does not extensively broaden the transition thermotropic profile of pure lipids, except for bilayers of DMPC where TAM induces a significant broadening detected with the two probes. In fluid liposomes of sarcoplasmic reticulum lipids and native membranes, TAM induces an ordering effect, as evidenced by Py(3)Py, failing DPH to detect any apparent effect as observed for the fluid phase of liposomes of pure lipid bilayers. These findings confirm the hydrophobic nature of tamoxifen and suggest that the localization and effects of TAM are modulated by the order and fluidity of the bilayer. These changes in the dynamic properties of lipids and the non-specific interactions with membrane lipids, depending on the order or fluidity of the biomembrane, may be important for the multiple cellular effects and action mechanisms of tamoxifen.

Animals↗
PubMed1988

Studies on effects of tamoxifen (ICI 46474) on agonistic encounters between pairs of intact mice.

The anti-estrogen tamoxifen (Tam), which has been shown to dramatically suppress offensive behavior in male rats without markedly influencing other aspects of the social encounter, was tested for its effectiveness in mice. TO strain albino mice were given control injections or 50 or 100 micrograms of Tam for 4 or 8 days. Subsequently, mice were tested in pairs (for a particular dose and treatment duration) in which both animals received Tam, one animal received Tam and one saline, or both animals received saline control injections. Ten-minute videotaped encounters were analyzed in terms of total times allocated to nonsocial investigation, social investigation, offense, defense, sexual activity/intense social investigation, and immobility. The lower dose given for the shorter duration produced less social investigation and more nonsocial investigation when Tam-treated subjects were paired together (cf. the Tam vs saline pairing). At all the other doses and durations, Tam reduced offense. Defense also changed in those pairings, but that activity seemed related to the amount of attack received. Tamoxifen had little influence on the weights of accessory sex glands. The data confirm that Tam is a potent suppressor of "androgen-dependent" aggression in male laboratory mice and provide further support for the aromatization hypothesis.

Aggression↗
PubMed1984

Anti-steroid action in cultured L-929 mouse fibroblasts.

L-929 mouse fibroblast growth is arrested by the glucocorticosteroid dexamethasone (dex), which also decreases adhesiveness to culture plates. Both dex effects were abolished when RU 486, a new synthetic anti-hormonal steroid, was added to the culture medium. Using [3H]RU 486, binding studies revealed that RU 486 bound approximately 25,000 sites/cell of the glucocorticosteroid receptor (GR) with affinity higher than that of dex and translocated GR to the nucleus. However, the distribution of steroid-receptor complexes between cytosol and nuclei was different for the agonist and the antagonist, with more nuclear accumulation in the case of dex. Estradiol increases L-929 cell growth and adhesiveness to culture plates, but not if the anti-estrogen tamoxifen (tam) was added. These observations initially made in serum containing medium, were confirmed in serum-free, chemically defined culture medium (SF). In SF medium, tam (1 microM) provoked death of most L-929 cells after 10 days of culture, leading to the selection of a variant clone LB of tam-resistant cells. Tam binds to the estrogen receptor (ER), but with less affinity than estradiol. ER concentration, estimated by the binding of 4-hydroxytamoxifen (OH-tam) and of estradiol was lower in LB cells than in original tam-sensitive L-929 cells. The concentration of specific anti-estrogen binding sites in the particulate fraction of the cells, measured by OH-tam binding, non competed by estradiol, was also significantly diminished in tam-resistant LB cells.

Animals↗
PubMed1985

Biological activities of tamoxifen aziridine, an antiestrogen-based affinity label for the estrogen receptor, in vivo and in vitro.

Tamoxifen aziridine (TA), an antiestrogen-based affinity label for the estrogen receptor, is highly selective and efficient in its covalent binding to the estrogen receptor (Katzenellenbogen et al., J. biol. Chem. 258 (1983) 3487-3495). Thus, it was of interest to investigate the biological character and potency of this compound and, in particular, to determine if the irreversible attachment of this tamoxifen-derived compound to the estrogen receptor would result in enhanced antiestrogenic properties or in unusual biological activity. The effect of tamoxifen aziridine and tamoxifen (Tam), the parent compound which is an antiestrogen that binds reversibly to the estrogen receptor, were compared with respect to their effects on uterine growth, growth of dimethylbenzanthracene (DMBA)-induced mammary tumors in rats, and proliferation and plasminogen activator activity of MCF-7 human breast cancer cells. In immature (day 20) rats, Tam and TA behaved as weak estrogen agonists and estrogen antagonists in that Tam or TA alone increased uterine weight to levels lower than that evoked by estradiol (E2), and both were able to suppress the stimulation of uterine weight evoked by E2. Administration of Tam and TA via Alzet minipumps (25 or 200 micrograms/rat/day) to mature rats bearing DMBA-induced mammary tumors resulted in marked regression and/or disappearance of most tumors. Uterine weights were also suppressed in these mature rats by Tam and TA. Tam was slightly more potent than TA in evoking tumor regression and in suppressing uterine weights in these in vivo studies. In MCF-7 human breast cancer cells in culture, Tam and TA suppressed cell proliferation and evoked no increase in plasminogen activator activity by themselves, while being very effective in preventing plasminogen activator activity stimulation by E2. Thus, TA displayed a bioactivity profile similar to that of Tam, the reversibly binding ligand, in vitro and in vivo. The covalent attachment of TA to the receptor does not, therefore, markedly alter the biological character or potency of the antiestrogen receptor complex.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

The effects of diethylstilbestrol, tamoxifen, and toremifene on estrogen-inducible hepatic proteins and estrogen receptor proteins in female rats.

Alterations of estrogen-inducible hepatic proteins and estrogen receptor proteins were studied in female rats after daily oral administration of vehicle control (0.5% carboxymethylcellulose), the nonsteroidal antiestrogens tamoxifen (TAM; 3, 11, or 45 mg/kg body weight), toremifene (TOR; 3, 12, or 48 mg/kg body weight), or the potent synthetic estrogen diethylstilbestrol (DES; 10 mg/kg body weight) for 1 and 3 months. Serum corticosterone levels were significantly reduced by TAM 11, TOR 12, and DES at 1 month and by TOR 48 and DES at 3 months. Serum ceruloplasmin levels were unchanged at 1 month except for a significant reduction with TOR 48 and a significant increase in the DES-treated group. After 3 months, all doses of TAM and TOR had significant reductions whereas DES had elevations even greater than those at 1 month. The activity of the enzyme alanine aminotransferase in the liver was increased by TAM, TOR, and DES at 1 and 3 months of treatment. Both TAM and TOR caused a slight reduction in cytosolic estrogen receptor protein after 1 month and significant reductions at 3 months. The nuclear estrogen receptor (nER) protein levels were significantly increased at 1 and 3 months for TAM and TOR; whereas DES treatment resulted in nER levels no different than controls. In summary, chronic (up to 3 months) administration of TAM and TOR results in qualitatively and quantitatively similar hormone-related effects on the female rat liver. Thus, other mechanisms must be investigated to ascertain the hepatoproliferative differences seen with TAM administration but not with TOR.

Alanine Transaminase↗
PubMed1995

Interaction of tamoxifen with cytosolic and nuclear type II estrogen binding sites (type II EBS).

The aim of this study was to investigate the interaction of tamoxifen (TAM) with the so-called Type II estrogen binding sites (Type II EBS) in both the cytosolic and the nuclear fraction of the ER-negative A 2780 human ovarian cancer cell line and in an ER-negative ovarian cancer tissue. Although cytosolic and nuclear Type II EBS in A 2780 cells showed substantially similar binding characteristics in terms of ligand affinity and specificity, TAM, while exhibiting the ability to displace [3H]estradiol from cytosolic Type II EBS failed to interact with nuclear Type II EBS. The ability of TAM to interact only with cytosolic Type II EBS seems also to be a characteristic of ovarian cancer tissue and to be shared by several TAM metabolites. The hypothesis that the interaction of TAM with cytosolic Type II EBS could mobilize the true endogenous ligand of Type II EBS which would become available for binding to nuclear Type II EBS was tested by incubating the nuclear fraction with the cytosolic fraction. In the presence of cytosol, TAM acquires the ability to displace the tracer from nuclear Type II EBS but when the cytosolic fraction was DCC, stripped in order to remove the endogenous ligand, the competing activity of TAM for nuclear Type II EBS was abolished. Our results suggest that TAM does not interact with nuclear Type II EBS, but can favor the nuclear binding of endogenous ligand by displacing it from cytosolic Type II EBS.

Binding Sites↗
PubMed1996

Effect of tamoxifen on intraperitoneal N-nitroso-N-methylurea induced tumors.

The effect of tamoxifen (TAM) was evaluated on a mammary tumor model induced in Sprague-Dawley rats by intraperitoneal administration of three N-nitroso-N-methylurea (NMU) doses. Animals received TAM (1 mg/kg per day) from 10 days before the first NMU dose up to 140 days later. Thereafter, treatment was discontinued and the observation period was extended 60 days longer. Mean overall latency period, tumor number per rat and tumor incidence were recorded. Significant differences between treated and control batches were observed in tumor number per rat (1.8 +/- 1.1 versus 5.2 +/- 1.6; P < 0.05) and in tumor incidence (50% versus 100%; P < 0.05), respectively. No significant difference in latency period between both batches was recorded. All lesions induced in the control batch were malignant, whereas only 45% of those induced in TAM-treated animals were malignant and the remaining 55% were preneoplastic. At 60 days after treatment discontinuance, tumor incidence increased to 90% and also tumor number per rat increased to 4.6 +/- 1.5. TAM effect was also evaluated in rats with NMU-induced tumors by treatment with 1 mg/kg per day during 60 days starting when tumors reached a 1.5-cm diameter. Regression to less than 80% of initial size in 49% of the tumors was observed, while in ovariectomized rats, 33% of tumors regressed. Estrogen receptor content, ER (fmol/mg protein) and Kd (nM) in control tumors were: 56 +/- 10 and 0.5 +/- 0.1. In tumors of TAM-treated animals, ER was less than 5 fmol/mg protein. Findings demonstrate that TAM significantly decreased the appearance of tumors induced in rats by i.p. injection of NMU and when TAM treatment was initiated after tumor induction, some tumors failed to respond to hormonal manipulation. Differential tumor growth response after TAM or oophorectomy in each tumor indicates that in the same rat it is possible to distinguish hormone-dependent and hormone-autonomous tumor populations. Hormonal regulation of tumor growth can be under intrinsic control, regardless of the hormonal status of the whole organism.

Animals↗
PubMed1996

Synergistic effects of tamoxifen and cepharanthine for circumventing the multidrug resistance.

We examined the synergistic effects of tamoxifen (TAM) and cepharanthine (CEP) for doxorubicin (DOX) sensitivity using MTT assay. The augmentation of DOX sensitivity by TAM and CEP was significantly correlated with the P-glycoprotein expression. The cytotoxic effect of DOX with TAM and CEP was significantly higher than that of DOX alone, or DOX with TAM, and this synergistic effect was dominant in cell lines with high expression of P-glycoprotein. It was also examined that the intracellular concentration of DOX was increased in combined exposure of TAM and CEP, compared with the exposure of TAM, because TAM and CEP promoted the influx and inhibited the efflux of DOX. Thus, TAM and CEP might be able to circumvent DOX-resistance for treatment in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Reaction of superoxide with trityl radical: implications for the determination of superoxide by spectrophotometry.

Superoxide radicals can be measured by redox methods which utilize the oxidation/reduction reactions of specific compounds. The redox methods, however, suffer from various interferences, which limit their use in the assay of superoxide. Electron paramagnetic resonance (EPR) spectroscopy using spin traps has been widely used as an alternative and direct technique to measure superoxide radicals. In our recent study, we have demonstrated the detection of superoxide in cellular system by EPR spectroscopy with triarylmethyl (trityl) free radical, TAM Ox063. TAM is highly water-soluble and stable in the presence of many biological oxidizing and reducing agents such as hydrogen peroxide, ascorbate, and glutathione. TAM reacts with superoxide with an apparent second order rate constant of 3.1x10(3)M(-1)s(-1). In the present work, we investigated the feasibility of a spectrophotometric assay of superoxide by taking advantage of the newly formed distinct absorption peak corresponding to the product formed from the reaction between TAM and superoxide. The effects of different fluxes of superoxide and concentrations of TAM on the efficiency and sensitivity of quantification of superoxide were investigated and compared with the widely used cytochrome c method of superoxide determination. The results demonstrated that the TAM method is comparable to the cytochrome c method for the assay of superoxide and further revealed that the assay is not affected by the presence of hydrogen peroxide. In summary, the TAM spectrophotometric assay of superoxide provides a suitable alternative method to the cytochrome c assay to measure superoxide and further complements our earlier reported TAM-EPR assay of superoxide.

Ascorbic Acid↗
PubMed2005

Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines.

The present study was designed to investigate the modulatory effect of the anti-estrogen, tamoxifen (Tam) on epirubicin (Epi) cytotoxicity in breast cancer cell lines; MCF-7 and NCI-adr. Using sulphorhodamine-B assay, NCI-adr cell line was found to be five-folds more resistant to the cytotoxic effect of Epi as compared to MCF-7 cell line. Pretreatment of cells with Tam was observed to enhance Epi cytotoxicity by 4.3- and 6.5-folds in MCF-7 and NCI-adr cells, respectively. Tam-Epi interaction was found to be additive in MCF-7 cells and synergistic in NCI-adr cells. Flowcytometric DNA ploidy analysis revealed that, Epi induced cell arrest at G2/M phase. Tam pretreatment enhanced the blocking activity of low dose of Epi in MCF-7 and induced nearly two-fold increase in the percentage of S phase in NCI-adr cells. Determination of cellular Epi level revealed that Tam induced a significant increase in intracellular Epi accumulation only in NCI-adr cells after 48 h. However, analysis of P-gp function revealed that Tam failed to modulate P-gp function in both cell lines. Also, assessment of topoisomerae IIalpha gene expression showed that neither Epi nor Tam managed to change its expression level. In conclusion, Tam potentiates Epi cytotoxicity in sensitive and resistant breast cancer cell lines. This potentiation can be explained by an enhancement of cell accumulation in S and G2/M phase, at which the cells are most sensitive to the cytotoxic effect of Epi as well as an increase in the intracellular level of Epi in resistant cell line.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Reversal of tamoxifen resistant breast cancer by low dose estrogen therapy.

Currently, the standard of care for estrogen receptor (ER)-positive breast cancer is 5 years of tamoxifen (TAM) or an aromatase inhibitor (AI) such as anastrozole. New studies indicate that extending antiestrogen therapy beyond 5 years with sequential regimens will improve disease-free survival. Based on the emerging concept that longer therapies are better, we have developed sequential models of tamoxifen-resistant breast cancer in vivo to mimic the clinical scenario of long-term antiestrogen therapy. The goal of the current study was to investigate the consequences of long-term treatment with tamoxifen on the growth of breast tumors in athymic mice. The results demonstrate that there are distinct phases of resistance to tamoxifen that correlate with time of treatment and expression of HER2/neu mRNA. In the treatment phase, 17beta-estradiol (E2) stimulated growth, while TAM inhibited growth of MCF-7 tumors (MCF-7E2). The withdrawal of treatment, mimicking the use of an AI, completely prevented growth. In Phase I resistance, the tumors (MCF-7TAMST) were growth-stimulated by either E2 or TAM, but inhibited by no treatment, fulvestrant, or E2 + fulvestrant. Phase II-resistant tumors (MCF-7TAMLT) were treated for more than 5 years and growth-stimulated by TAM. However, no treatment, fulvestrant, or E2 completely inhibited growth. Interestingly, the few tumors (MCF-7TAMLT) that survived in response to E2 were robustly re-stimulated by E2 after transplantation into new generations of athymic mice. These E2-stimulated tumors (MCF-7TAME) were inhibited by TAM in a dose-dependent similar to their parental tumors (MCF-7E2). In addition, the MCF-7TAME tumors were inhibited by either no treatment or fulvestrant. HER2/neu and HER3 mRNAs were over-expressed in TAM-stimulated MCF-7TAMLT tumors and remained high in E2-stimulated MCF-7TAME tumors. The data indicate that complete reversal of resistance to TAM can be achieved with the use of low dose E2 therapy. Also, these data suggest that over-expression of HER2/neu alone is insufficient to predict resistance to TAM. Based on the results, we suggest using an alternating treatment regimen, cycling antiestrogen with estrogen therapy to avoid drug-resistance.

Animals↗
PubMed1998

Effects on mouse uterus of three antitumoral drugs acting upon estrogen and progesterone receptors directly and through other transduction pathways.

Three antitumoral drugs, tamoxifen (Tam), medroxyprogesterone acetate (MPA), and 8-Cl-cyclic AMP (8Cl), were administered separately and in combination to normal adult mice in order to record their effects on uterus weight, on estrous cycle, and on two estrogen receptor (ER) and progesterone receptor (PgR) parameters, namely content and nucleo-cytoplasm distribution. Tam decreased uterus weight (49%) and total ER content (118+/-6 vs 328+/-20 fmol/mg protein in controls) but increased total PgR (1183+/-230 vs 743+/-52 fmol/mg protein in controls) and nuclear retention of ER and PgR. MPA down-regulated PgR content and increased uterus weight (36%), but failed to modify ER and PgR nuclear retention. The only parameter changed by 8Cl was nucleo-cytoplasm PgR distribution. Tam + MPA association produced the same results as Tam alone for ER and PgR nuclear retention, but receptor content was not significantly different from that of controls. Both drugs, administered separately, had opposite effects on PgR content; when both were acting concurrently, an algebraic addition of effects was observed, as if both transcription circuits were triggered independently. Remaining Tam effects, not modified by a combination with MPA, indicated the predominance of Tam on the corresponding parameters. When Tam and 8Cl were administered together, 8Cl counteracted the effect of Tam only on PgR content. When associated with MPA, 8Cl changed the effects of MPA on ER and PgR nuclear retention, whereas on receptor content, only that of ER was increased (502+/-47 vs 328+/-20 fmol/mg protein in controls). These crossed effects indicate that interrelations between different transduction pathways can affect certain functional circuits while sparing others. The possibility of acting pharmacologically upon different transcription pathways represents a novel approach to modify drug effects directed to specific transduction targets through cross-talk between their components.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Characterization of the major DNA adducts in the liver of rats chronically exposed to tamoxifen for 18 months.

Our previous study has shown that chronic exposure to tamoxifen (TAM) induced formation of high levels of DNA adducts in the liver, the target tissue of TAM-induced carcinogenesis in rats. One of the major DNA adducts (spot 1), as detected by 32P-postlabeling, accounted for 53% of the total adducts. To characterize this major adduct, the current study has compared spot 1 with two previously identified TAM-DNA adducts, i.e. alpha-TAM-N2-deoxyguanine (alpha-TAM-N2-dG) and alpha-N-desmethyl TAM-N2-deoxyguanine (alpha-N-dmTAM-N2-dG) by various rechromatography methods. It was found that spot 1 was further resolved into two fractions during rechromatography analysis, one fraction co-migrated with the alpha-TAM-N2-dG and the other fraction co-migrated with the alpha-N-dmTAM-N2-dG. These findings have demonstrated that chronic exposure to tamoxifen induced the same major DNA adducts, i.e. alpha-TAM-N2-dG and alpha-N-dmTAM-N2-dG as those detected in acutely exposed rats.

Animals↗
PubMed1999

Effect of a half dose of tamoxifen on proliferative activity in normal breast tissue.

OBJECTIVES: To investigate the proliferative activity of the mammary gland epithelium and plasma levels of progesterone, estradiol, prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) in premenopausal women treated with 10 and 20 mg of tamoxifen (TAM) for 22 days. PATIENTS AND METHODS: A randomized double-blind study was performed with 43 premenopausal women with a diagnosis of fibroadenoma of the breast. The patients were divided into three groups: A (n = 15, placebo); B (n = 15, TAM 10 mg/day) and C (n = 13, TAM 20 mg/day). They started taking an oral dose of TAM or placebo on the very first day of the menstrual cycle. Lumpectomy was performed on the 22nd day of therapy. Normal breast tissue samples were collected during surgery, immediately immersed in 10% buffered formalin, processed for routine histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) detection. Two peripheral blood samples were collected, both on the 22nd day of the menstrual cycle, in order to evaluate the hormone levels. PCNA expressing epithelial cells were quantified by using a digital program Kontron Image System KS-300 in 1000 cells (400 x ). RESULTS: The percentage of cells expressing PCNA was significantly higher in the group receiving placebo (group A, 50.3%) when compared to groups receiving TAM 10 or 20 mg/day (group B, 24.1%; and group C, 23.2%, respectively) (P < 0.001). Differences between groups B and C were not significant. Levels of progesterone, estradiol and SHBG were significantly higher in B and C groups compared to group A. Increasing concentrations of FSH (P < 0.0045) and lower levels of prolactin (P < 0.0055) were only found in the group receiving 20 mg/day of TAM (group C). CONCLUSIONS: A 22-day TAM therapy, either with 10 or 20 mg/day, significantly reduced the PCNA expression and therefore the proliferative activity of the normal human breast tissue. Increasing levels of estradiol, progesterone and SHBG were associated with TAM therapy at 10 or 20 mg/day. However, a significant change of the level of FSH and prolactin was reached only with a 20-mg/day dose.

Adolescent↗
PubMedDate not supplied

Tamoxifen prevents sulpiride-induced weight gain in female rats.

To evaluate its potential utility in counteracting neuroleptic-induced obesity, the effects of long-term administration of tamoxifen (TAM) on body weight (BW) and food intake (FI) of gonadally intact and sulpiride-treated (SUL) female rats were assessed. In addition, estradiol and prolactin serum levels were measured in rats treated with SUL. SUL plus TAM and SUL plus bromocriptine (BR). TAM, at doses of 10, 50 and 100 micrograms, significantly decreased BW gain: FI was significantly reduced at the doses of 50 and 100 micrograms. In addition, doses of TAM ranging from 5-100 micrograms completely prevented SUL-induced BW gain and hyperphagia. BR also prevented SUL effects on BW and FI. In contrast to BR, concomitant administration of TAM did not prevent SUL-induced hyperprolactinemia. Estradiol levels were not modified by SUL alone or SUL plus BR, but they were significantly increased in the animals treated with TAM plus SUL. Neuroleptic-induced obesity in female rats might be related to an alteration in gonadal steroid balance secondary to hyperprolactinemia. While BR might counteract neuroleptic-induced weight gain by preventing hyperprolactinemia, TAM might directly interact with estrogen receptors, or indirectly increase estradiol levels. The use of TAM in preventing neuroleptic-induced obesity in humans warrants further investigation.

Animals↗