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PubMed2005

Integrative analysis of gene expression patterns predicts specific modulations of defined cell functions by estrogen and tamoxifen in MCF7 breast cancer cells.

To explore the mechanisms whereby estrogen and antiestrogen (tamoxifen (TAM)) can regulate breast cancer cell growth, we investigated gene expression changes in MCF7 cells treated with 17beta-estradiol (E2) and/or with 4-OH-TAM. The patterns of differential expression were determined by the ValiGen Gene IDentification (VGID) process, a subtractive hybridization approach combined with microarray validation screening. Their possible biologic consequences were evaluated by integrative data analysis. Over 1000 cDNA inserts were isolated and subsequently cloned, sequenced and analyzed against nucleotide and protein databases (NT/NR/EST) with BLAST software. We revealed that E2 induced differential expression of 279 known and 28 unknown sequences, whereas TAM affected the expression of 286 known and 14 unknown sequences. Integrative data analysis singled out a set of 32 differentially expressed genes apparently involved in broad cellular mechanisms. The presence of E2 modulated the expression patterns of 23 genes involved in anchors and junction remodeling; extracellular matrix (ECM) degradation; cell cycle progression, including G1/S check point and S-phase regulation; and synthesis of genotoxic metabolites. In tumor cells, these four mechanisms are associated with the acquisition of a motile and invasive phenotype. TAM partly reversed the E2-induced differential expression patterns and consequently restored most of the biologic functions deregulated by E2, except the mechanisms associated with cell cycle progression. Furthermore, we found that TAM affects the expression of nine additional genes associated with cytoskeletal remodeling, DNA repair, active estrogen receptor formation and growth factor synthesis, and mitogenic pathways. These modulatory effects of E2 and TAM upon the gene expression patterns identified here could explain some of the mechanisms associated with the acquisition of a more aggressive phenotype by breast cancer cells, such as E2-independent growth and TAM resistance.

Breast Neoplasms↗
PubMed1992

Transient abnormal myelopoiesis in Down's syndrome.

Recent data have elucidated the pathogenesis of transient abnormal myelopoiesis (TAM) to a great extent. TAM is a monoclonal disorder which resolves spontaneously and the target cell in this disorder is a multipotent stem cell which is capable of differentiating into megakaryocytes. The pathogeneses of TAM/AMKL (acute megakaryoblastic leukemia) appears to be closely associated with abnormal quality and quantity of a gene located on chromosome 21. AMKL developing after the regression of TAM appears to come from the same clone as the TAM, which apparently experiences some kind of genetic alterations. It seems that the gene responsible for TAM will soon be cloned in the near future. However, the mechanism of spontaneous regression of TAM has as yet not been clarified. The expanding clone in the transient physiological immunodeficient state, during the perinatal period, might be eliminated with the maturation of more mature immunosurveillance. Alternatively, the TAM clone might be destined to undergo spontaneous death, which is called "programmed cell death" (apoptosis). The mechanism of this phenomenon awaits further elucidation.

Chromosome Aberrations↗
PubMed1998

Antagonist effect of insulin-like growth factor I on protein kinase inhibitor-mediated apoptosis in human glioblastoma cells in association with bcl-2 and bcl-xL.

OBJECT: Tamoxifen (TAM) has been found to be effective in inhibiting proliferation of glioblastoma cells in vitro, but clinical studies have been disappointing. The purpose of this study was to determine whether insulin-like growth factor I (IGF-I), a potential autocrine/paracrine mitogen produced by glioblastomas, interferes with the antimitogenic actions of TAM. METHODS: Human glioblastoma cells were treated with or without TAM and/or IGF-I in vitro and evaluated for: viability by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenol tetrazolium bromide cleavage assay; apoptosis by histochemical analysis of nuclear morphology and 3'-OH DNA fragments; and expression of the IGF-I receptor, and the bcl-2, bcl-xL, and bax proteins by immunoblot analysis. In addition, p53 status was determined by DNA sequencing and by transient transfection with luciferase reporter plasmids containing wild-type or mutant p53. Results indicated that after 72 hours of exposure to 2 mg/ml TAM in vitro, 56.3% of WITG3 and 43.8% of U87-MG glioblastoma cells contained apoptotic nuclei (p < 0.01 compared with untreated cells). Apoptosis was independent of the presence of p53 because the WITG3 cells, in contrast to the U87-MG cells, expressed a mutant, nonfunctional p53. The WITG3 cells expressed IGF-I receptor proteins and demonstrated IGF-I binding. Exogenous IGF-I stimulated WITG3 cell proliferation and significantly (p < 0.05) antagonized the cytotoxic effects of TAM in a dose-dependent fashion; IGF-I, but not TAM, enhanced expression of bcl-2 and bcl-xL proteins; however, bax protein expression was unchanged by either treatment. CONCLUSIONS: Because many gliomas secrete large amounts of IGF-I in autocrine/paracrine growth pathways, these data may, in part, explain the failure of TAM to achieve clinical results as dramatic as those in vitro.

Antineoplastic Agents, Hormonal↗
PubMed1999

[A randomized study of adjuvant treatments for operable breast cancer patients stratified by estrogen receptor and menopausal status].

According to estrogen receptor (ER) and menopausal status, operable breast cancer patients were randomized for adjuvant endocrine therapy with tamoxifen (TAM) in premenopausal patients, after oophorectomy (OVEX), chemotherapy, CHEM (mitomycin C+ oral cyclophosphamide), or chemo-endocrine therapy (TAM + CHEM). Some 1579 patients were entered in the trial between 9, 1978 and 12, 1991, with a median follow-up of 10 years. In ER-positive, premenopausal patients there were no significant differences in relapse-free (RFS) or overall survival (OS) among the OVEX + TAM, CHEM, and CHEM + TAM arms. On the contrary, in ER-positive, post-menopausal patients, the chemoendocrine therapy showed a significantly better OS (p = 0.0254) with a trend of better RFS (p = 0.0674), as compared with TAM or CHEM groups. ER-negative, premenopausal patients showed no significant differences in RFS or OS between CHEM and CHEM + TAM arms. In ER-negative, postmenopausal patients, there was a non-significantly better RFS (p = 0.0888) and a significantly better OS (p = 0.0332) in CHEM + TAM group than in the CHEM alone group. These results suggest that ER and menopausal status are important criteria to select early breast cancer patients for adjuvant treatments.

Adult↗
PubMed2000

Inhibitory action on GHRH-induced GH secretion of chronic tamoxifen treatment in breast cancer.

OBJECTIVE: Previous in vitro and in vivo studies on animal models have demonstrated that tamoxifen (TAM) inhibits GH secretion. Studies in humans are conflicting. The aim of this study was to evaluate the effect of chronic TAM treatment on GH secretory dynamics in the presence of negligible endogenous oestrogens, in postmenopausal women with breast cancer. PATIENTS: Ten female patients were studied over a 6-12-month period after surgical therapy, before medical therapy, and during chronic treatment with TAM (20 mg/day p.o.). MEASUREMENTS: In all subjects we performed a standard GHRH-test (50 mg i.v. as a bolus) and compared the single time points, the peak response and the areas under the curves (AUC), before and during treatment. In basal samples, we evaluated the circulating levels of IGF-1, IGF-BP3 and their ratio, SHBG, FSH, LH, Oestradiol (E2) and PRL. GH was assayed by Immunoradiometric assay (IRMA). Insulin-like growth factor type I (IGF-I), Insulin-like growth factor-binding protein-3 (IGF-BP3), FSH, LH and PRL were measured by Radioimmunoassay (RIA). SHBG was measured by a noncompetitive liquid phase immunoradiometric assay, while E2 was measured directly in plasma by a liquid phase technique. RESULTS: TAM chronic treatment significantly reduced GH response to GHRH at single time point evaluations, GH peak response (mean decrease: 59.8 +/- 7.3%) and GH-AUC (mean decrease 53.8 +/- 8.9%). TAM also significantly reduced plasma IGF-1 levels. No significant variations were found in IGF-BP3 levels or in the IGF-1/IGF-BP3 ratio. A significant inverse correlation between SHBG and IGF-1 circulating levels was noticed during TAM treatment. CONCLUSIONS: Our data show that long-term tamoxifen treatment blocks the response of GH to exogenous GHRH and reduces IGF-1 levels, possibly by a central mechanism other than the demonstrated peripheral action. The results of this study, keeping in mind the demonstrated mitogenic role of IGF-1 in cancer proliferation, can contribute to clarify the mechanism by which TAM exerts its antiproliferative effect.

Aged↗
PubMedDate not supplied

Effect of 5alpha-dihydrotestosterone implants on the fertility of male rats treated with tamoxifen.

In adult male rats, tamoxifen (TAM) reduces circulating levels of luteinizing hormone (LH) and testosterone (T) with no effect on follicle-stimulating hormone (FSH) and prolactin (PRL). It reduces the male rat's ability to inseminate the female (potency), as well as its siring ability (fecundity). The objective of the present study was to test whether androgen supplementation could reverse all or some of the observed effects of TAM. To obviate the effects of estrogen, the study was designed to evaluate the beneficial or deleterious effect of 5alpha-dihydrotestosterone (DHT), a 5alpha-reduced, nonaromatizable metabolite of T, on the reproductive functions of TAM-treated adult male rats. Adult male rats received either saline or TAM (0.2 or 0.4 mg per day p.o.) for 90 days. A group of TAM-treated rats was implanted with 6 mg DHT from day 50 to day 90. A third group of untreated animals was implanted with 0-, 1-, 3-, or 6-mg DHT implants for 90 days. Mating studies were done to assess the fecundity, potency, and fertility index at the end of the treatment. Weights of testes, pituitary, and accessory sex organs were recorded, and circulating levels of LH, FSH, PRL, T, and 17-beta-estradiol were estimated. DHT did not affect the fecundity or fertility index. TAM reduced fecundity, potency, and the fertility index. DHT implants improved the fertilizing ability of the TAM-treated male rat. This study discusses and reviews the role of T and 17-beta-estradiol in sperm-fertilizing potential in light of these observations.

Animals↗
PubMed2000

Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen.

The risk of developing endometrial cancer increases significantly for women treated with tamoxifen (TAM); the present study was designed to investigate the mechanism of this carcinogenic effect. Endometrial tissue was obtained from 16 women treated for varying lengths of time with TAM and from 15 untreated control subjects. DNA was analyzed with a (32)P-post-labeling/HPLC on-line monitoring assay capable of detecting 2.5 adducts/10(10) nucleotides. Using this sensitive and specific assay, TAM-DNA adducts were detected in eight women. The major adducts found were trans and cis epimers of alpha-(N(2)-deoxyguanosinyl) tamoxifen (dG-N(2)-TAM); levels ranged between 0.2-12 and 1.6-8.3 adducts/10(8) nucleotides, respectively. There was marked inter-individual variation in the relative amounts of cis and trans adducts present. Low levels (0.74-1.1 adducts/10(8) nucleotides) of trans and cis forms of dG-N(2)-TAM N-oxide were detected in one patient. DNA adducts derived from 4-hydroxytamoxifen quinone methide were not observed. We conclude from this analysis that trans and cis dG-N(2)-TAMs accumulate in significant amounts in the endometrium of many, but not all, women treated with this drug. The level of adducts found, coupled with the previous demonstration of their mutagenicity [Cancer Res., 59, 2091, 1999], suggest that a genotoxic mechanism may be responsible for TAM-induced endometrial cancer.

Adult↗
PubMed2001

Analysis of cross-resistance of the selective estrogen receptor modulators arzoxifene (LY353381) and LY117018 in tamoxifen-stimulated breast cancer xenografts.

PURPOSE: Cross-resistance is the primary issue facing the evaluation of new antiestrogens to treat metastatic breast cancer because they may be tested, initially, in populations of patients that have failed long-term adjuvant tamoxifen (Tam) therapy. EXPERIMENTAL DESIGN: We have tested the benzothiophene derivatives, arzoxifene (Arzox; LY353381) and LY117018 in two models of Tam-stimulated tumor growth derived from either MCF-7 (M. M. Gottardis and V. C. Jordan, Cancer Res., 48: 5183-5187, 1988) or T47D (J. MacGregor Schafer et al., Clin. Cancer Res., 6: 4373-4380, 2000) breast cancer cells. RESULTS: Using the MCF-7:Tam model, we found that both Arzox and LY117018 (1.5 mg/day) resulted in tumor growth and, therefore, were partially cross-resistant with Tam. Next, using the T47D:17beta-estradiol (E(2)) model, we compared the antiestrogenic/antitumor properties of Arzox and LY117018 and determined that neither Arzox nor LY117018 caused T47D:E(2) tumor growth after 21 weeks. In addition, we determined that long-term treatment does not result in failure and subsequent development of transplantable Arzox- or LY117018-stimulated tumors. To establish whether Arzox and LY117018 are cross-resistant in T47D:Tam tumors, mice were treated with Arzox or LY117018 (1.5 mg/day), and, again, we found that neither resulted in the growth of transplantable tumors. Lastly, we showed that Arzox and LY117018 were only partially able to compete with postmenopausal E(2) (0.3 cm silastic capsule) in T47D:Tam tumors. However, when T47D:E(2) tumors were treated for 7 days instead of 5 days, both Arzox and LY117018 were more effective. CONCLUSIONS: Arzox is not cross-resistant with Tam in the T47D athymic mouse model but does exhibit cross-resistance in the MCF-7 model.

Animals↗
PubMed2002

[Effect of mitogen-activated protein kinase signal transduction in non-estrogen antagonistic mechanism of tamoxifen].

OBJECTIVE: To investigate the effect of mitogen-activated protein kinase (MAPK) signal cascade in the non-estrogen antagonistic mechanism of tamoxifen (TAM). METHODS: Human breast cancer cells MCF-7 were cultured. TAM, PD98075, inhibitor of MAPK kinase (MEK), or TAM + PD98075 was added into the culture media, followed by methyl thiazolyl tetrazolium (MTT) and DMSO. Then the 542nm absorption value was measured and the growth curve was drawn. Western blot was used to measure the expression of p-extracellular signal-regulated kinase (ERK) in MCF-7 cells. Flow cytometry was applied to analyze the cell cycle and apoptosis. RESULTS: The optical density representing the relative expression of p-ERK was lower successively in the control, TAM, PD09875, and TAM + PD09875 groups. The apoptotic rate of MCF-7 cells was 6.44%, 8.3%, 36.5% and 53.5% in the control, PD98075, TAM, and TAM + PG98075 groups respectively The rate of cells in G(0)G(1) phase was 74.25%, 79.76%, 84.02%, and 95.82% in those groups respectively. Ther rate o cells in S phase was 21.03%, 15.22%, 11.43%, and 2.22% respectively in those groups. The rate of cells in G(2)M phase was 4.71%, 5.02%, 4.52%, and 1.96% respectively in those groups. CONCLUSION: MAPK signal transduction pathway plays a certain role in the non-estrogen antagonistic mechanism of tamoxifen.

Antineoplastic Agents, Hormonal↗
PubMed1992

Tamoxifen suppresses tumor promoter-induced hydrogen peroxide formation by human neutrophils.

Trans-tamoxifen (TAM) has been used successfully in therapy for estrogen-dependent human breast tumors and prevention of their recurrence. The mechanism of this prevention was thought to be due to the interference of TAM with estrogen promotion. TAM has a wider anticarcinogenic action that is similar to other chemopreventive agents in that it suppresses tumor promotion in 2-stage carcinogenesis by interfering with the action of protein kinase C. We report that TAM (5 microM) totally inhibits hydrogen peroxide (H2O2) formation by 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-treated human neutrophils. Interestingly, beta-estradiol (10 microM) also slightly inhibits the oxidative burst of neutrophils. Pretreatment of neutrophils with varying amounts of TAM and beta-estradiol caused additive inhibition of H2O2 formation by the 2 agents. 4-Hydroxy-tamoxifen, a metabolite with the highest affinity for the estrogen receptor, was only as inhibitory as beta-estradiol. Other derivatives (cis-, N-desmethyl-, and N-desdimethyl-tamoxifen) with low biological activities had a smaller effect on H2O2 formation. TPA-treated neutrophils were shown to contain 5-hydroxymethyl uracil (HMU). TAM prevented the TPA-induced formation of HMU in other cells. Like TPA, dietary fat, which is a risk factor for breast cancer, induces formation of HMU in the DNA of human white blood cells. TAM may suppress the dietary fat-induced HMU in the same manner at it does in TPA-induced neutrophils.

Estradiol↗
PubMed2006

Interleukin-2 augmented activation of tumor associated macrophage plays the main role in MHC class I in vivo induction in tumor cells that are MHC negative in vitro.

The contribution of tumor associated macrophage (TAM) to the induction of major histocompatibility complex (MHC) class I expression in vivo has not been reported precisely. In this study, we utilized Interleukin-2 (IL-2) cDNA-introduced B16 melanoma cells (B16/IL-2) and vehicle-alone control cells (B16/mock) to examine whether TAM could contribute to the induction of MHC class I on B16 cells in vivo. Interestingly, although B16/mock and B16/IL-2 did not express MHC class I in vitro, MHC class I was strongly expressed in vivo in B16/IL-2 in comparison to B16/mock. Although in vivo treatment of anti-NK1.1 antibody abolished MHC expression in B16/mock in vivo, the same treatment did not influence MHC expression in B16/IL-2. Interestingly, both anti-asialo GM1 and anti-CD11b treatment strongly decreased MHC expression in B16/IL-2. TAM expressed both asialo GM1 and CD11b antigen, and TAM recovered from B16/IL-2 produced interferon gamma (IFNgamma) 6 times more than that from B16/mock. In addition, TAM recovered from B16/IL-2 secreted 33.64 times more IFNgamma in response to in vitro administration of IL-2. Therefore, we checked whether or not IL-2 could influence the expression of IL-2 receptors. TAM recovered from IL-2 expressed middle affinity receptor of IL-2 (CD122 and CD132) while that from B16/mock expressed low affinity receptor (CD25 and CD132). Finally, we observed that B16 cells became apoptotic with IFNgamma treatment in vitro. These results suggested that IL-2 augmented activation of TAM would play the main role in induction of the MHC class I molecule through secretion of IFNgamma, and would contribute to the IFNgamma-mediated apoptosis induction in tumor cells.

Animals↗
PubMedDate not supplied

Effect of rosiglitazone on N-nitroso-N-methylurea-induced mammary tumors in rat.

The objective of this study was to evaluate the in vivo antitumor action of rosiglitazone (Rosi) alone or in combination with tamoxifen (Tam) on experimental mammary tumors induced by N-nitroso-N-methylurea (NMU) in Sprague-Dawley rats. Animals bearing mammary tumors were treated with 0.06 mg/kg/day or 0.12 mg/kg/day of Rosi orally, 1 mg/kg/day of Tam s.c., or with the combined treatment (Rosi+Tam). After 25 days of treatment, the following responses were observed: 45% of tumors were responsive to 0.06 mg/kg/day of Rosi treatment, while 55% of tumors under Tam treatment responded. The results of the combined Rosi+Tam treatment indicated that 75% of tumors were responsive. Similar results were obtained with 0.12 mg/kg/day of Rosi. Apoptosis, necrosis and glandular hypersecretion were observed in Rosi-treated tumors. In all cases, the combined Rosi+Tam treatment potentiated the antitumor effect of Tam alone. No side-effects were observed after treatment at any assayed dose.

Animals↗
PubMed1990

A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas.

Tumor-associated macrophages (TAM) isolated from two murine sarcomas (mFS6 and MN/MCA1) had high levels of proliferative activity (7 to 11% of cells in S phase) compared to peritoneal macrophages (1 to 2% of cells in S phase). In an effort to elucidate the mechanisms responsible for the proliferative activity of TAM, expression of c-fms and macrophage (M)-CSF was investigated in TAM and sarcoma cells. TAM had high levels of mRNA transcripts of the c-fms protooncogene, which encodes a tyrosine kinase probably identical to the M-CSF receptor, but did not express M-CSF transcripts whereas sarcoma cells had high levels of M-CSF mRNA. Sarcoma cell conditioned medium had M-CSF activity on bone marrow cells and induced proliferation of peritoneal exudate and bone marrow-derived macrophages. These activities were blocked by anti-M-CSF antibodies. These findings outline a paracrine circuit in the regulation of TAM proliferation, involving M-CSF, secreted by sarcoma cells and acting on c-fms expressing TAM. Inasmuch as TAM from these murine sarcomas have tumor growth promoting activity, a "ping pong" reciprocal feeding interaction may occur between macrophages and neoplastic cells in these tumors.

Animals↗
PubMedDate not supplied

Comparative fates of clomiphene and tamoxifen in the immature female rat.

The triarylethylene antiestrogens clomiphene (CLO) and tamoxifen (TAM) have each been shown to be converted in vitro to "active" metabolites which may contribute to their antiestrogenic effects. We have studied the disposition of CLO and TAM in the immature female rat, the animal model with which the majority of biochemical studies of the effects of antiestrogens have been conducted. Both drugs were eliminated mainly by the feces after ip administration, with CLO being eliminated three times as efficiently (57%) as TAM (19%) over 24 hr. Most of the dose of CLO was eliminated unchanged; most of the dose of TAM was eliminated as metabolites, especially 4-hydroxy-TAM. TAM was accompanied by an array of metabolites in liver and uterine tissues 24 hr after ip injection. In contrast, injection of CLO resulted in negligible recoveries from these tissues of metabolites demonstrated to be produced in the presence of liver microsomal homogenates. Instead, a polar material of unidentified composition accompanied unchanged CLO in these tissues. These results reconfirm the fact that the effects of TAM are due in part to its metabolites and suggest that, in contrast, the effects of CLO are due mainly to unchanged drug.

Animals↗
PubMed1989

Effect on growth and cell cycle kinetics of estradiol and tamoxifen on MCF-7 human breast cancer cells grown in vitro and in nude mice.

The effects of estradiol and tamoxifen (TAM) on the estrogen-dependent human breast cancer cell line MCF-7 grown in vitro and in nude mice were compared. The effect on growth was determined by cell number in vitro and by tumor growth curves in nude mice. The effects on the cell cycle kinetics were determined by repeated flow cytometric DNA analyses in vitro and in vivo and by the technique of labeled mitosis in nude mouse-grown tumors. Under in vitro conditions, estradiol induced a pronounced increase in S-phase fraction and cell number. TAM inhibited growth of MCF-7 cells with a concomitant increase in the G1 phase from 60% to 75%. In nude mice, MCF-7 only formed tumors in estradiol-supplemented mice. No differences were observed in growth and cell kinetics between 0.1 and 1.0 mg of estradiol. Daily i.p. injections of TAM resulted in tumor growth inhibition with shrinkage of tumors. The flow cytometric DNA analysis and percentage of labeled mitosis investigations revealed no significant differences in the proliferation kinetics of TAM-treated and control tumors. Calculating the cell loss factor demonstrated an increase from 69% in control tumors to 107% in TAM-treated tumors. These experiments have shown that the cell kinetic effect of TAM is different when MCF-7 cells are grown in vitro versus in vivo. In contrast to the in vitro data, the in vivo data indicate that the growth-inhibitory effect of TAM is not mediated through a perturbation of the cell cycle.

Animals↗
PubMed1988

[The role of adjuvant endocrine therapy in the management of operable breast cancer].

UNLABELLED: Since June, 1982, a chemoendocrine adjuvant clinical trial has been conducted at the Aichi Cancer Center Hospital. Women with operable breast cancer were stratified on the basis of the number of positive axillary nodes. Node negative patients received tamoxifen (TAM) for 6 months (Trial I), patients with 1-7 positive nodes received either cyclophosphamide (CPA) for 4 weeks and TAM for one year (Trial II), and patients with 8 or more positive nodes received either CPA for 8 weeks and TAM for 3 years (Trial III). Numbers of evaluable cases are 449 for Trial I, 228 for Trial II and 84 for Trial III. This is an interim report, and the median follow-up time is 3 years and 5 months. This is a prospective non-randomized trial, and control groups (observation group and chemotherapy group) are historical. RESULTS: 1. Premenopausal patients in Trial I yielded intermediate outcome between those of observation and chemotherapy groups. Thus, for this subgroup, adjuvant chemotherapy can be considered as a standard, and addition of TAM is recommended. 2. The benefit of TAM is apparent for postmenopausal patients in Trial I. 3. TAM is effective for both pre- and postmenopausal patients in Trial II. Addition of more aggressive chemotherapy should be considered. 4. Premenopausal patients in Trial III had a better disease-free survival compared with those of control groups. More effective combined chemotherapy may yield longer overall survival. 5. Postmenopausal patients in Trial III had a better disease-free and overall survival rate. Adjuvant TAM and combined chemotherapy can be considered as standard care for this subgroup.

Adjuvants, Immunologic↗
PubMed1987

[Metastatic breast cancer. Modality of association of chemotherapy and hormonotherapy. Results of a controlled trial].

Two hundred forty-seven patients with metastatic breast cancer entered into the controlled trial. Its aim was to define the optimal modality of association between hormonotherapy and chemotherapy. Chemotherapy was given a monthly course of an association including: adriamycin: 45 mg/m2 on day 1; cyclophosphamide: 400 mg/m2 on days 1, 2, 3; 5 fluoro-uracil: 500 mg/m2 on days 1, 2, 3; methyl-prednisolone: 80 mg/m2 on days 1, 2, 3. Hormonotherapy was tamoxifen (TAM) at the daily dose of 30 mg. 82 patients in group I were given TAM alone for 4 months and then chemotherapy + TAM; 83 patients in group II were given simultaneously TAM + chemotherapy; 82 patients in group III were given chemotherapy alone for 8 months and then TAM + chemotherapy. The response rates in groups I, II and III were respectively of 59, 74 and 62%. The difference in favour of group II was marginally significant. The survival curves were significantly higher in group II and III than in group I (P = 0.04). This result appears as the consequence of the poor prognostic of the sub-group of 45% patients who did not respond to TAM. These results seem to emphasize that target cells of hormonotherapy are not target cells of chemotherapy and that this difference is persisting for long time under treatment, that others modalities of association between chemotherapy and hormonotherapy must be studied with the aim of reducing the kinetic's implication of chronic administration of TAM.

Adult↗
PubMedDate not supplied

Antiestrogen binding sites in human breast cancer biopsies. Measurement ligand-specificity and affinity, and correlation to estrogen and progesterone receptors.

Specific binding sites for the antiestrogen tamoxifen (AEBStot), as measured with the dextran-coated charcoal technique and Scatchard analysis, were quantitated in 43 of 44 breast cancer samples (41-2,100 fmol/mg protein). In this work, AEBStot has been defined as the sum of AEBSspec and estrogen receptor (ER), AEBSspec shows a very weak positive correlation with ER, and no correlation with progesterone receptor. Tamoxifen (TAM) has a lower affinity to ER compared with one of its main metabolites, 4-OH-TAM. This may be one reason why inhibition by excess estradiol on 3H-4-OH-TAM binding was better correlated with ER content in the same sample than if 3H-TAM was the radioactive ligand. It is therefore suggested that 3H-4-OH-TAM is a better choice than 3H-TAM for measuring AEBSspec alone. A possible role of AEBSspec for the clinical effects of TAM is discussed.

Breast Neoplasms↗