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PubMedDate not supplied

Effects of tamoxifen, medroxyprogesterone acetate and estradiol on tumor growth and oncogene expression in MCF-7 breast cancer cell line transplanted into nude mice.

The effects of three hormonal agents with a different mechanism of action (tamoxifen [TAM], medroxyprogesterone acetate [MPA] and estradiol [E2]) on tumor growth, differentiation and oncogene expression were evaluated using the estrogen-receptor positive human breast carcinoma cell line MCF-7 transplanted into nude mice. In MCF-7 tumors treated with E2, tumor incidence, mean weight of tumors, 3H-thymidine labelling index, differentiation antigen HMFGM (human milk-fat globule membrane) and ras p21, c-myc, neu oncogene products, the level was significantly increased. On the other hand MPA suppressed all of them. TAM increased the level of c-myc expression and HMFGM antigen, but suppressed the others. This evidence indicates that E2 induces both proliferation and differentiation of MCF-7 tumor cells. MPA suppresses both proliferation and differentiation, and TAM induces differentiation and suppresses proliferation.

Animals↗
PubMed1991

[Indications for allogeneic and autologous bone marrow transplantation].

In bone marrow transplantation (BMT) the main reason for early treatment failure is transplant-associated mortality (TAM) due to GvHD, interstitial pneumonia, veno-occlusive disease and infections. Since 1981, 84 consecutive HLA-identical BMT have been performed (13 aplastic anemia, 61 leukemia/lymphoma, 3 genetic diseases; mean age 28 [5-51] years) according to a standardized protocol designed to reduce TAM: fractionated, low dose rate irradiation; strict laminar air flow isolation plus complete intestinal decontamination; cyclosporine therapy for 4 months and CMV prophylaxis (hyperimmune plasma infusion, CMV-negative blood products). 11 patients (13%) died in TAM. Continuous complete remission was obtained in 78% of standard risk patients (n = 55) and 28% of high risk patients (n = 29). Mean observation time was 42 (3-116) months post transplantation. This result points to the necessity of a liberal indication for BMT early in the course of acute or chronic myelogenous leukemia, in the course of acute or chronic myelogenous leukemia, severe aplastic anemia and other eventually lethal hemato-oncological diseases.

Adolescent↗
PubMed1990

Effects of sequential and combined endocrine therapies on the growth of 7,12-dimethylbenz [alpha] anthracene-induced rat mammary carcinoma.

Sixty-six female Sprague-Dawley (SD) rats with 7,12-dimethylbenz [alpha] anthracene(DMBA)-induced rat mammary cancer were divided into five groups: tamoxifen (TAM), medroxyprogesterone acetate (MPA), TAM + MPA, ovariectomy (Ovex), control (no treatment). An antitumor effect was shown in each treated group. Thirty-six (72%) out of 50 treated animals responded to the first endocrine therapy. Moreover, tumors disappeared completely from 21 out of the 36 animals, and no new tumors were seen until the 12th week. The facts suggest experimental hormone, when compared to clinical, therapy in DMBA-induced tumors to have a higher response rate. A total of 14 out of 50 tumors failed to respond to the first treatment (resistant tumor). There was no significant difference in the proportion of resistant tumors among the four treated groups. When other endocrine therapies were tried out of resistant tumors, seven out of the 14 responded, the resistant tumors in the TAM group responding significantly well to the other endocrine therapies compared to those in the MPA group (P less than 0.05). These results suggest the possibility of resistant tumors responding to different types of endocrine therapy.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

Tumor bed effect in murine tumors: relationship to tumor take and tumor macrophage content.

This study investigated whether the clonogenic ability of tumor cells to establish subcutaneous tumors and the tumor-associated macrophage (TAM) content correlate with the development and extent of the tumor bed effect (TBE). Ten tumors, five sarcomas and five carcinomas, syngeneic to C3Hf/Kam mice were used. Tumors were grown subcutaneously in the right thighs of mice that had or had not been irradiated with 20 Gy of gamma rays 1 day before tumor cell transplantation. Of the 10 tumors, 7 exhibited a significant TBE. The severity of the TBE, which varied greatly among these tumors, was significantly positively correlated (correlation coefficient = 0.81) with TD50 values (i.e., the number of tumor cells needed to produce tumors in 50% of injected sites). In addition, a trend toward a negative correlation between degree of TBE and TAM content was apparent. The implication of these results is that tumors with high clonogenic ability (low TD50 values) and high macrophage content are less likely to demonstrate the TBE. The data suggest that tumor angiogenic potential, provided by both tumor cells and TAM, is an important parameter in the development of the TBE.

Animals↗
PubMed1990

[Human breast cancer cells under serum-free culture. Its hormone-dependency and application to the primary culture].

Assessment of hormone-dependency of breast cancer cells in human to estradiol (E2) and progesterone (Pg) has been made by making serum-free culture of the cells, and primary culture of breast cancer cells is made by this method. The results are as follows: 1. E2 promotes proliferation of estrogen receptor (ER)-positive cells in low concentrations but rather inhibits it in high concentrations. This inhibitory effect is also observed in ER-negative cells. If the mode of this inhibitory effect is compared with the cellular dynamics of Tamoxifen (TAM) which binds predominantly to ER, the cellular dynamics of E2 in high concentrations resembles that of TAM, from which some influence being exerted on the binding site of TAM by high concentrations of E2 is presumed. 2. At binding of E2 to ER, S phase fraction increases significantly for 24 hours of culture if analyzed from the cellular dynamics, proving that the binding occurs comparatively in a short period. 3. Inhibition of cellular proliferation by PgR depends on the concentration. PgR is not induced with only E2, and interference of other factors is suggested in the induction. 4. Proliferation of the initially cultured cells is promoted by E2 although ER is present or not.

Breast Neoplasms↗
PubMed1989

[Influence of endocrine therapy on the proliferation of estrogen (ER) positive cells and ER negative cells of human breast cancer (MCF-7)].

The influence of endocrine therapy on the proliferation of estrogen receptor (ER) positive cells and ER negative cells of human breast cancer (MCF-7) serially transplanted into nude mice was analyzed by tumor growth, dextran-coated charcoal (DCC) method, ER-immunocytochemical assay (ER-ICA) and ER-immunocytochemically stained 3H-thymidine autoradiography. In the tamoxifen (TAM) group and the medroxyprogesterone acetate (MPA) group, tumor growth was inhibited, but it was promoted in the 17 beta-estradiol dipropionate (E2) group. The ER level by the DCC method significantly decreased in the TMA, the MPA and the E2 groups. The ER-ICA showed that the ER positive cells rate in the TAM and the MPA group decreased, but it increased in E2 group. However, the ER-immunocytochemically stained 3H-thymidine autoradiography showed that not only the labelling index of ER-positive cells but also that of ER negative cells significantly decreased in the TAM and the MPA groups, but significantly increased in the E2 groups. Therefore it was concluded that endocrine therapy affected the proliferation of both ER positive cells and ER negative cells of ER positive breast cancer.

Animals↗
PubMed1987

Cell surface phenotyping of megakaryoblasts.

Surface phenotypic characterization of megakaryoblasts, identified by platelet peroxidase activity, was investigated in four patients who showed increased proliferation of megakaryoblasts: one patient with typical features of acute leukemia, one presenting with acute myelofibrosis, and two with Down's syndrome in whom blasts disappeared spontaneously (transient abnormal myelopoiesis, TAM). MY10 and/or MY9 antigens were expressed on the surface of some megakaryoblasts, but MY7, and MY4, antigens specific to granulocytic or monocytic cells, were not. Some megakaryoblasts were positive for only anti-HLA-DR antibodies. It was speculated that, during the differentiation of the megakaryocytic lineage, MY9 antigen appears transiently on the surface of megakaryoblasts that have lost HLA-DR antigens and have gained the glycoprotein IIb/IIIa antigen. This study also demonstrated that the proliferating blasts in some patients with TAM were mainly megakaryoblasts and suggested that the target cells in TAM are CFU-GEMM.

Adolescent↗
PubMed1987

[Hormone-dependency of human breast cancer in in vitro clonogenic assay].

The in vitro clonogenic assay has been used to assess the biological effects of estradiol-17 beta (E 2) and an antiestrogen, tamoxifen (TAM) on human breast cancer, and the results were compared with the estrogen receptor status (ER). The sera used were treated with dextran-coated charcoal to avoid the modification effects of the endogenous hormones. There was a significant difference between ER (+) and ER (-) breast cancers in the incidence of cases in which the plating efficiency of cancers increased more than 50% over those of untreated control by adding 10(-8) M of E 2 (40.2% vs. 21.3%). TAM, 10(-6) M revealed a less than 50% colony formation of the control in 30.5% of ER (+) cancers, whereas only 13.0% of ER (-) cancers showed a response to TAM.

Breast Neoplasms↗
PubMedDate not supplied

Mode of estrogen action on cell proliferation in CAMA-1 cells: III. Effect of antiestrogen.

Estrogen (E) stimulatory effects on mammary carcinoma are well documented; however, little is known of the precise mechanism regulating E-induced cell proliferation. This study attempts to investigate the in vitro effects of E and antiestrogen (AE) on promoting cell proliferation and the cell cycle kinetics of an experimental mammary carcinoma model, CAMA-1. Sublines IR and IN, which have been shown to respond to E somewhat differently in 3H-thymidine (3H-dThd) uptake and in the induction of progesterone receptor (Cancer Res 41: 5004-5009, 1981), were evaluated concurrently. The present report showed that E stimulated and AE, as shown by tamoxifen (TAM) and nafoxidine hydrochloride (NAF), inhibited cell growth and 3H-dThd uptake in a dose-related manner for both sublines supplemented with serum. In a chemically defined medium with 1% steroid-stripped serum, the E-stimulatory effect was nullified, and cells were more sensitive to AE. These results suggest that serum component(s) is (are) involved in AE and E action. The TAM inhibition could be partially reversed by E. A partially synchronized G1 population, arrested by serum deprivation for 48 hrs, responded promptly to E stimulation. While E promoted a faster G1 exit, faster for IN cells than for IR subline, AE inhibited cell progression at the G1 phase. Furthermore, E stimulated a higher proportion of S-phase formation during the first cycle of hormone treatment while AE inhibited this process. These results are consistent with the notion that TAM and E act on some common events at the G1 phase in cell proliferation. The net result of E stimulation was the promotion of new cell to traverse the cell cycle, the acceleration of G1 exit, and an increase in the proportion of S-phase and dividing cells per cycle. In contrast, AE inhibited the progression of cells at the G1 phase, resulting in a marked decrease of S-phase and dividing cells per cycle. Our results also demonstrate the importance of careful kinetic studies in evaluating the E and AE responses of mammary carcinoma cells in culture, and this is best conducted with synchronized populations.

Animals↗
PubMed1987

[Proliferation kinetics of MCF-7 cell cultures. I. Relative influence of estrogens and antiestrogens on the growth of the cell population].

The cellular hormone dependent cell line MCF-7 is a tumoral model of mammary cancer the growth kinetics of which operating under the influence of varied and opposed hormonal factors (estrogens and antiestrogens at precise concentration levels) has provided the means of knowing the action mechanisms of such agents. In this study, carried out with cultured MCF-7 cells under well defined experimental conditions, it has been shown that: 1) antiestrogens (OH-TAM) seem to be opposed to the growing process of the cellular population the elements of which, under the influence of OH-TAM, double the value of the parameter TD (Doubling Time); 2) estrogens (17-beta-E2) cancel out this effect and promote the growth of MCF-7 cells whether OH-TAM is previously or simultaneously added to the culture medium; 3) the observation of this estrogenic action needs accurate experimental conditions without which the effect may not be seen.

Cell Division↗
PubMed1985

[Preliminary report of adjuvant chemo-endocrine therapy for breast cancer].

Preliminary analysis of adjuvant chemo-endocrine therapy for 193 breast cancer patients was performed. The patients consisted of 38 cases of Stage I, 124 cases of Stage II and 31 cases of Stage III. Therapeutic regimen was randomly divided into three groups; (1) Tamoxifen (TAM), (2) TAM + ftorafur (FT-E) and (3) TAM + FT-E + Adriamycin. Side effects among the three therapeutic groups were comparatively studied. Anorexia and nausea were observed in 1.4%, 17.1% and 60% of the patients, respectively. Leucopenia of less than 3,000 and alopecia were remarkably seen in the patients treated with regimen 3. Liver dysfunction was observed in 10.9% of group 1, 29.5% of group 2 and 13.3% of group 3, respectively. Gastrointestinal symptoms and liver dysfunction were important side effects.

Adult↗
PubMed1983

[Transitory abnormal myelopoiesis of the monoblastic form in a newborn infant with Down's syndrome and liver cirrhosis].

A case of 5-day old newborn infant with trisomy 21, who presented a leucocytosis (151 000/ml) with 60% of monoblasts and marked hepatosplenomegaly is reported. Transient abnormal myelopoiesis (TAM) was retained. TAM regressed spontaneously. However the baby died at the age of 50 days. The autopsy showed extramedullary hematopoiesis with marked monocytosis and liver cirrhosis of neonatal hepatitic origin. The pathogenesis of TAM in this case was discussed.

Bone Marrow↗
PubMed1984

[Experimental and clinical study on endocrine therapy of breast carcinoma, with special reference to the nuclear estrogen receptor].

The effects of hormones on growths and estrogen receptor (ER) processing were investigated on human breast carcinomas. Two human breast carcinomas, Br-10 (ERC +,ERn-,PgR-) and MCF-7 (ERc +,ERn +,PgR +), serially transplanted into nude mice were used for the experiments. The tumors were treated with estrogen (E) and/or progesterone (P) or tamoxifen (TAM). Although the growth of Br-10 was enhanced by EP and arrested by TAM, ER processing which was observed by E and EP was also observed temporarily by TAM in the early stage, however it was suppressed subsequently. The growth of MCF-7 was dependent on E and the suppression of ER processing was observed in MCF-7 which was transplanted into nude rats and maintained without hormonal treatment. Accordingly, it was suggested that ER processing could be altered by changes in hormonal environment of hosts. ER translocation by priming the exogenous estrogen in vitro was studied in clinical cases. Whereas ERn was detected in 3 out of 20 cases, ER processing was observed in 10 out of 17 ERc positive breast carcinomas (58.8%) and none observed in 3 ERc negativities.

Adult↗
PubMed1995

Synthesis and biological evaluation of basic side chain derivatives of Analog II as pure antiestrogens and antitumor agents.

In an effort to prepare effective non-steroidal antiestrogens without intrinsic estrogenicity and with greater antagonism than those of the triarylethylenes (tamoxifen; TAM) four N-substituted (Z)-1,1-dichloro-2-[4-(2-aminoethoxy)phenyl]-3-phenylcyclopropa ne derivatives of the antiestrogen, Analog II, in which the basic side chains contain cyclic (piperidino and piperazino) and non-cyclic (dimethyl amino and diethyl amino) moieties, were synthesized. These compounds were prepared from an intermediate methanesulfonyloxyethoxy side chain ester of 1,1-dichloro-2,3-cis-diphenylcyclopropane using their respective side chain bases in triethylamine and acetonitrile. The gem-dichloro-cis-diarylcyclopropane derivatives were tested for their ability to inhibit the growth-stimulating effect of estradiol on immature mouse uteri and the growth of estrogen receptor (ER)-positive MCF-7E3, ER-negative MDA-MB-231 and the ER-positive MCF-7LY2 antiestrogen-resistant breast cancer cells in culture. The introduction of the various aminoethoxy side chains into Analog II did not improve its ER-binding affinity. Like Analog II, the derivatives did not exhibit any intrinsic estrogenicity, and compounds 9 and 10 antagonized estradiol action more completely than the parent compound. None of the compounds potentiated the uterine weight gain from the stimulating dose of estradiol (0.03 micrograms). Derivatives 9 (150 micrograms), 10 (150 micrograms) and 11 (150 micrograms) had uterine mean weights significantly below the estradiol-treated group, and were better antagonists than Analog II and MER25 at the same concentrations. All compounds exhibited a statistically significant (P < 0.01) reduction in control growth (antitumor activity) from 0.01 to 10 nM concentration in the MCF-7E3 cells. At 10 nM concentration, 8 (66%) and 9 (64%) had the greater antitumor activity over 10 (58%) and 11 (58%). No activity in this cell line was observed for Analog II, TAM and ICI 182,780. Antitumor action was also demonstrated in the MDA-MB-231 cells for all derivatives at 1.0 microM dose, with 9 having the greatest (27%) inhibition of control growth, followed by 8 (20%), 10 (18%) and 11 (12%). Analog II and ICI 182,780 had no antitumor activity in this cell line, while TAM exhibited only 8% inhibition. In the MCF-7E3 cell line at 1.0 microM, 9 exhibited 86% inhibition of the estradiol-stimulated growth (antiestrogenic activity), followed by 8 (64%), 10 (52%) and 11 (21%).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Dominant negative mutant of c-Jun inhibits NF-AT transcriptional activity and prevents IL-2 gene transcription.

Expression of the transcription complex AP-1, composed of Jun and Fos family members, can be induced by a variety of stimuli. In lymphocytes, AP-1 transcriptional activity increases after TCR ligation and plays an important role in T cell activation events such as lymphokine secretion. To explore the requirements for AP-1 in IL-2 production, the AP-1 complex was targeted with a dominant negative mutant c-Jun protein, TAM-67, from which the transactivation domain has been deleted. In transient transfections of Jurkat cells, TAM-67 efficiently inhibited endogenous AP-1 transcriptional activity and blocked the activity of a reporter construct containing the 5' regulatory region of the IL-2 gene. TAM-67 also inhibited the transcriptional activity of nuclear factor-AT (NF-AT), whereas the NF-kappa B, NF-IL-2A, and the proximal TRE-like sites were relatively unaffected. The use of this dominant negative transcription factor suggests that: 1) transactivation-defective nuclear factors represent a novel approach to study the functional consequences of nuclear protein interactions on gene transcription; 2) the proximal TRE-like site from the IL-2 promoter is different from the consensus TRE; and 3) AP-1 plays an important role in the transcriptional activation mediated by the NF-AT binding complex.

Base Sequence↗
PubMed1994

Leiomyomas in patients receiving Tamoxifen.

In literature there have been only 8 cases of unavoidable laparotomy due to uterine leiomyomas performed in patients with breast cancer on Tamoxifen (TAM). Our article describes two cases of rapidly growing leiomyomas in patients treated with TAM: one of these underwent abdominal hysterectomy while the second stopped taking TAM and began therapy with Triptorelin. This therapeutical alternative could be a useful choice.

Adult↗
PubMed1993

Transient abnormal myelopoiesis of infancy associated with trisomy 21.

PURPOSE: A unique myelodysplastic syndrome referred to as transient abnormal myelopoiesis (TAM) has been reported to occur primarily in infants with Down's syndrome (DS) or other abnormalities of chromosome 21. This disorder raises basic questions regarding the pathogenesis of leukemia, yet its natural history is poorly documented and derives from small series and isolated case reports. PATIENTS AND METHODS: To better characterize TAM, we accumulated data on 35 cases identified through a questionnaire mailed to pediatric oncologists in the United States. These cases, pooled with two that we recently encountered, and 58 comparable cases reported in the literature comprise a series of 95 cases of TAM in DS. RESULTS: The patients in this series were notable for the high morbidity and mortality of this reportedly benign condition. Eleven percent of the patients died during the initial event, and the overall mortality for the entire series was 27%. Twenty-eight of the 85 patients (33%) who survived the initial event developed a subsequent hematologic disorder, most often acute nonlymphocytic leukemia, at a median age of 16 months. CONCLUSIONS: No initial clinical or hematologic features predicted the development of a subsequent hematologic disorder. However, those patients initially mosaic for the presence of trisomy 21 did not develop subsequent abnormalities. This series reviews questions regarding leukemogenesis in DS and underscores the importance of conducting future prospective studies of this unique hematologic disorder.

Chromosome Aberrations↗
PubMed1993

[Antitumor activity of a new antiestrogenic drug, toremifene (NK622) against human breast cancer xenografts in nude mice].

NK622, a novel tamoxifen(TAM) analog with nonsteroidal structure is an antiestrogenic drug with less toxicity compared with that of TAM. We studied the in vivo antitumor activity against human breast cancer xenografts in nude mice. NK 622 significantly inhibited the growth of estrogen-dependent Br-10 breast cancer but not inhibited the growth of estrogen-independent MC-2-JCK and MC-5-JCK when orally administered once daily for 14 days at the maximum tolerated dose (200mg/kg/day). The dose of NK622 in animal studies was calculated by measuring plasma level in patients receiving 40 mg/body/day oral treatment and clinically equivalent dose (CED) was determined. At the calculated CED, NK622 significantly inhibited the growth of Br-10. These results indicate that NK622 is a promising drug comparable to TAM because of the growth inhibition of estrogen-dependent breast cancers.

Animals↗