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PubMed2004

Right ventricular long-axis function in relation to left ventricular systolic function.

A decrease in left ventricular (LV) systolic function is accompanied by a decrease in maximal relaxation velocity in LV long-axis direction, but is it also accompanied by a decrease in right ventricular (RV) long-axis function? To study this 35 consecutive patients were examined by echocardiography. Ejection fraction (LVEF) and mitral annulus motion (MAM) were used as indices of LV systolic function and tricuspid annulus motion (TAM), that is the systolic shortening in RV long-axis direction, was used as an index of RV systolic long-axis function. In the same way the maximal relaxation velocity in LV long-axis direction, that is the maximal diastolic velocity of MAM (MDV MAM), has been suggested as an index of LV diastolic function the maximal diastolic velocity of TAM (MDV TAM) can be supposed to be an index of RV diastolic function measuring the maximal relaxation velocity in the RV long-axis direction. A significant positive correlation was found between MDV TAM and MAM (r = 0.64, P<0001) and LVEF (r = 0.54, P = 0.001) and between TAM and the two studied indices of LV systolic function, with the highest correlation to MAM (r = 0.68, P<0.001) and the lowest to LVEF (r = 0.57, P<0.001). Thus, a decrease in LV systolic function is accompanied by a decrease in both systolic and diastolic RV long-axis function, findings that probably are due to the close anatomical connection between the ventricles and to changes that occur in afterload of the RV secondary to LV systolic dysfunction.

Aged↗
PubMed2002

Neuronal differentiation and protection from nitric oxide-induced apoptosis require c-Jun-dependent expression of NCAM140.

c-Jun, a crucial component of the dimeric transcription factor activating protein 1 (AP-1), can regulate apoptosis induced by oxidative stress and has been implicated in neuronal differentiation, but the mechanisms are largely unknown. We found that specific inhibition of transcription or stable transfection with cDNA encoding dominant-negative c-Jun sensitized SH-SY5Y neuroblastoma cells (TAM-67 cells) to apoptosis induced by the nitric oxide (NO) donor sodium nitroprusside or SIN-1. TAM-67 cells also became refractory to nerve growth factor (NGF)-induced neuronal differentiation. Dominant-negative c-Jun abolished expression of a 140-kDa neural cell adhesion molecule (NCAM140) and dramatically enhanced the expression of NCAM180 in TAM-67 cells. Inhibition of c-Jun in TAM-67 cells also resulted in a corresponding decrease in the amount of NCAM140 mRNA and an increase in the amount of NCAM180 mRNA. Reexpression of NCAM140 in TAM-67 cells restored NGF-induced neuronal differentiation and resistance to NO-induced apoptosis. Our results show that c-Jun/AP-1, through up-regulation of NCAM140, plays an important role in both NGF-induced neuronal differentiation and resistance to apoptosis induced by NO in neuroblastoma cells. As NCAM140 and NCAM180 are translated from differentially spliced mRNAs transcribed from the same gene, alternative splicing of NCAM pre-mRNA (and consequently the synthesis of the smaller NCAM140 species) appears to be regulated by c-Jun/AP-1.

Apoptosis↗
PubMed2006

p50 nuclear factor-kappaB overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance.

Tumor-associated macrophages (TAM) are a major inflammatory infiltrate in tumors and a major component of the protumor function of inflammation. TAM in established tumors generally have an M2 phenotype with defective production of interleukin-12 (IL-12) and high IL-10. Here, we report that defective responsiveness of TAM from a murine fibrosarcoma and human ovarian carcinoma to M1 activation signals was associated with a massive nuclear localization of the p50 nuclear factor-kappaB (NF-kappaB) inhibitory homodimer. p50 overexpression inhibited IL-12 expression in normal macrophages. TAM isolated from p50(-/-) mice showed normal production of M1 cytokines, associated with reduced growth of transplanted tumors. Bone marrow chimeras showed that p50 inactivation in hematopoietic cells was sufficient to result in reduced tumor growth. Thus, p50 NF-kappaB overexpression accounts for the inability of TAM to mount an effective M1 antitumor response capable of inhibiting tumor growth.

Active Transport, Cell Nucleus↗
PubMed2001

Interrogation of the tricuspid annulus by Doppler tissue imaging in patients with chronic pulmonary hypertension: implications for the assessment of right-ventricular systolic and diastolic function.

BACKGROUND: Chronic pulmonary hypertension (CPHT) has a great impact on both right-ventricular (RV) systolic and diastolic properties and the assessment of those properties is not always feasible by traditional echocardiographic examination. Doppler tissue imaging (DTI) interrogation of the tricuspid annulus (TA) identifies the pattern of TA motion (TAM) and can help to assess RV function when other methods are not feasible. AIMS: To determine RV systolic and diastolic function in patients with CPHT using DTI parameters of the TA. METHODS: Eighty-seven patients with CPHT and 90 normal controls were studied. DTI parameters were measured including early diastolic, late diastolic and systolic velocities and time velocity integrals (TVI) of the TAM at both its lateral and medial aspect. RESULTS: Early diastolic and systolic velocities, the ratio of early to late diastolic velocities and TVI of TAM at both lateral and medial aspects were significantly decreased in patients with CPHT compared to controls. No significant differences were seen in late diastolic velocities and TVI in both groups. Systolic velocity of the TAM at both its lateral and medial aspects significantly correlated with RV systolic function as measured by fractional RV area change. CONCLUSIONS: DTI of the TAM can be used to assess RV systolic and diastolic properties in patients with CPHT.

Aged↗
PubMed2002

Comparison of plasma levels of mature adrenomedullin and natriuretic peptide as markers of cardiac function in hemodialysis patients with coronary artery disease.

BACKGROUND: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. PATIENTS AND METHODS: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. RESULTS: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = -0.756, p < 0.0001). CONCLUSIONS: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.

Adrenomedullin↗
PubMedDate not supplied

Effect of tamoxifen on pS2 expression in human breast cancers.

pS2 protein expression is induced by estrogen through estrogen receptors (ER), and is known to be inhibited by antiestrogen in the breast cancer cell line MCF-7. The present study was undertaken to determine whether pS2 expression may be inhibited by the antiestrogen tamoxifen (TAM) human breast cancer. pS2 expression was immunohistochemically investigated in 22 patients treated preoperatively with TAM and in 45 without TAM treatment (control group). Immunostaining was considered positive when 10% of tumor cells showed cytoplasmic staining. We found that 94% of the pS2-positive tumors were ER-positive (ER+), and there was a significant association between the two proteins (p < 0.0001). In ER+ tumors, pS2 expression was seen in only 21% (3 of 14) of the TAM+ group, compared to 70% (16 of 23) of the control group. Statistical analysis of these data indicated a high likelihood (p = 0.006) of TAM treatment being associated with inhibition of pS2 expression in human breast cancers.

Antineoplastic Agents, Hormonal↗
PubMed2006

Targeting tumor-associated macrophages as a novel strategy against breast cancer.

Tumor-associated macrophages (TAMs) are associated with tumor progression and metastasis. Here, we demonstrate for the first time that legumain, a member of the asparaginyl endopeptidase family functioning as a stress protein, overexpressed by TAMs, provides an ideal target molecule. In fact, a legumain-based DNA vaccine served as a tool to prove this point, as it induced a robust CD8+ T cell response against TAMs, which dramatically reduced their density in tumor tissues and resulted in a marked decrease in proangiogenic factors released by TAMs such as TGF-beta, TNF-alpha, MMP-9, and VEGF. This, in turn, led to a suppression of both tumor angiogenesis and tumor growth and metastasis. Importantly, the success of this strategy was demonstrated in murine models of metastatic breast, colon, and non-small cell lung cancers, where 75% of vaccinated mice survived lethal tumor cell challenges and 62% were completely free of metastases. In conclusion, decreasing the number of TAMs in the tumor stroma effectively altered the tumor microenvironment involved in tumor angiogenesis and progression to markedly suppress tumor growth and metastasis. Gaining better insights into the mechanisms required for an effective intervention in tumor growth and metastasis may ultimately lead to new therapeutic targets and better anticancer strategies.

Animals↗
PubMed2006

Monocyte/macrophage infiltration in tumors: modulators of angiogenesis.

The role of a tumor immune infiltrate in cancer progression and metastasis has been debated frequently. Although often considered to be associated with improved prognosis and leading to the enhanced survival of cancer patients, inflammatory cells have also been described to assist the tumor's capabilities to progress, proliferate, and metastasize. Tumor-associated macrophages (TAMs), for example, have been shown to be symbiotically related to tumor cells: Tumor cells recruit TAMs and provide them with survival factors, and TAMs in turn produce a variety of angiogenic factors in response to the tumor microenvironment. This review will describe the composition of an immune infiltrate in tumors and the angiogenic and angiostatic properties of the cells present. Special emphasis will be on the angiogenesis-associated activities of TAMs. The development of immunotherapy and gene therapy using TAMs to mediate tumor cytotoxicity or to deliver gene constructs will be discussed as well. As immunotherapy has so far not been as effective as anticipated, a combination therapy in which angiostatic agents are used as well is put forward as a novel strategy to treat cancer.

Angiogenesis Inhibitors↗
PubMed1989

Doxorubicin-containing regimens for the treatment of stage II breast cancer: The National Surgical Adjuvant Breast and Bowel Project experience.

Despite numerous reports of findings obtained following the use of doxorubicin (Adriamycin [A]; Adria Laboratories, Columbus, OH) for the postoperative treatment of patients with primary breast cancer and positive axillary nodes, no clear consensus exists regarding its worth when used in that setting. In June 1981, the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented two randomized clinical trials aimed at evaluating the worth of doxorubicin when administered in conjunction with melphalan (L-PAM) and fluorouracil (5-FU) (PF). A prior NSABP study identified cohorts of patients who did or did not benefit from tamoxifen (TAM, T) when used with chemotherapy. That information was employed in the design of the present studies. Women considered responsive to TAM (1,106) were randomized between PFT and PAFT, and those nonresponsive to TAM (707) were randomized between PF and PAF. Findings through 6 years of follow-up (mean duration of potential time on study, 64 months and 63 months, respectively) indicate that non-TAM-responsive patients who received PAF had a significantly better disease-free survival (DFS) (P = .003) and survival (P = .05) than did those receiving PF. By contrast, there was no significant difference in DFS (P = .6) or survival (P = .7) between PFT- and PAFT-treated patients. No disparity in the amount of drug received, whether related to the median amount or to dose-intensity, is present to account for the difference in findings between the studies. Aside from alopecia and emesis, the toxicity from the doxorubicin-containing regimens was similar to those in which doxorubicin was omitted. Cardiomyopathy was not a significant finding; there were no deaths from cardiac toxicity. The incidence of arterial and venous complications in patients receiving TAM was less than reported by others.

Aged↗
PubMed1994

First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. Swiss Group for Clinical Cancer Research.

PURPOSE: We performed a randomized phase III multicenter study to compare systemic treatment versus no treatment after complete excision and radiotherapy for isolated first locoregional recurrence in patients with breast cancer. PATIENTS AND METHODS: One hundred sixty-seven good-risk patients with an estrogen receptor (ER+) positive recurrence or, in case of unknown receptor status, a disease-free interval (DFI) of greater than 12 months and < or = three recurrent tumor nodules each < or = 3 cm in diameter were entered onto the study. They were randomized to observation subsequent to local treatment or to receive tamoxifen (TAM) until disease progression. Seventy-nine percent of the patients were postmenopausal. RESULTS: The median observation period for the entire study population was 6.3 years. The median disease-free survival (DFS) duration was 26 months for observation and 82 months for TAM patients (P = .007). This was mainly due to the reduction of further local recurrences, whereas the occurrence of early distant metastases was delayed. A multivariate analysis identified DFI and treatment with TAM as significant prognostic factors for DFS. The 5-year overall survival (OS) rates were 76% and 74%, respectively (P = .77). DFI was also a prognostic factor for OS. CONCLUSION: Systemic therapy with TAM after isolated locoregional recurrence of breast cancer significantly increased 5-year DFS rates from 36% to 59% compared with observation alone and prolonged median DFS by more than 4.5 years in patients with ER+ tumors or in the case of unknown ER status with a DFI of greater than 12 months and minimal tumor burden. Treatment with TAM currently has no significant impact on OS, but the median survival duration of the study population has not yet been reached.

Adult↗
PubMed1994

Tamoxifen: is it useful in the treatment of patients with metastatic melanoma?

PURPOSE: We have attempted to review the data regarding the activity of tamoxifen (TAM) to clarify the role of this agent in the treatment of metastatic melanoma. METHODS: Using the Melvyl Medline system, we identified recent reports describing the results of clinical trials that used TAM either as a single agent or in combination with other cytotoxic agents. Additionally, we reviewed the abstracts from the 29th Annual Meeting of the American Society of Clinical Oncology held in May 1993. RESULTS: Numerous articles have reported an overall response rate of 47% (95% confidence limit, 39.25 to 54.75) when patients with metastatic melanoma are treated with the combination of dacarbazine (DTIC), carmustine (BCNU), cisplatin (DDP), and TAM (DBDT). Additionally, recent laboratory studies have reported that synergism between TAM and DDP is at least partially responsible for the success of this regimen. CONCLUSION: While TAM as a single agent is minimally active in treating patients with metastatic melanoma, when it is combined with DTIC, BCNU, and DDP, a marked improvement in the overall response rate is observed. Although a prospective randomized trial has yet to be completed, it appears that this four-drug combination has a higher overall and complete response (CR) rate when compared with single-agent DTIC. In light of the relatively modest toxicity observed with this regimen, the combination of DBDT represents a reasonable alternative to single-agent DTIC as first-line therapy for patients with metastatic melanoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer.

PURPOSE: N-(4-hydroxyphenyl) retinamide (¿4-HPR, Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P </=.01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade </= 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean +/- SD Cp retinol was 708 +/- 280 ng/mL. Mean +/- SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 +/- 0.21 micromol/L, 0.28 +/- 0.21 micromol/L, and 282 +/- 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM. CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.

Administration, Oral↗
PubMed2003

The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro.

Although many estrogen receptor-positive breast cancers initially respond to antihormones, responses are commonly incomplete with resistance ultimately emerging. Delineation of signaling mechanisms underlying these phenomena would allow development of therapies to improve antihormone response and compromise resistance. This in vitro investigation in MCF-7 breast cancer cells examines whether epidermal growth factor receptor (EGFR) signaling limits antiproliferative and proapoptotic activity of antihormones and ultimately supports development of resistance. It addresses whether the anti-EGFR agent gefitinib (ZD1839/Iressa; TKI: 1 mum) combined with the antihormones 4-hydroxytamoxifen (TAM: 0.1 mum) or fulvestrant (Faslodex; 0.1 mum) enhances growth inhibition and prevents resistance. TAM significantly suppressed MCF-7 growth over wk 2-5, reducing proliferation detected by immunocytochemistry and fluorescence-activated cell sorter cell cycle analysis. A modest apoptotic increase was observed by fluorescence-activated cell sorter and fluorescence microscopy, with incomplete bcl-2 suppression. EGFR induction occurred during TAM response, as measured by immunocytochemistry and Western blotting, with EGFR-positive, highly proliferative resistant growth subsequently emerging. Although TKI alone was ineffective on growth, TAM plus TKI cotreatment exhibited superior antigrowth activity vs. TAM, with no viable cells by wk 12. Cotreatment was more effective in inhibiting proliferation, promoting apoptosis, and eliminating bcl-2. Cotreatment blocked EGFR induction, markedly depleted ERK1/2 MAPK and protein kinase B phosphorylation, and prevented emergence of EGFR-positive resistance. Faslodex plus TKI cotreatment was also a superior antitumor strategy. Thus, increased EGFR evolves during treatment with antihormones, limiting their efficacy and promoting resistance. Gefitinib addition to antihormonal therapy could prove more effective in treating estrogen receptor-positive breast cancer and may combat development of resistance.

Antineoplastic Agents, Hormonal↗
PubMed1983

The interaction of estrogen- and antiestrogen-receptor complexes with polynucleotides.

As the polynucleotide domain of the estrogen receptor (Re) is a possible site for the modulation of Re activity, the interaction of antiestrogen (4-hydroxytamoxifen and tamoxifen)-receptor complexes (4-OH-Tam-Re and Tam-Re) with polynucleotides (oligodeoxynucleotide-cellulose, DNA-cellulose, and polyribonucleotide-agarose) was investigated and compared with that of the 17 beta-estradiol-receptor complex (E2-Re). E2-Re- and anti-Re-E2-complexes were optimally bound to oligo(dT)-cellulose and poly(U)-agarose at 0.15 M KCl and pH 7.6. Temperature activation of the Re was not required for these selective interactions to occur, but they were inhibited by 10 mM sodium molybdate. OH-Tam-Re and E2-Re demonstrated similar selectivity for different deoxynucleotide bases [oligo(dG) greater than oligo(dT) greater than or equal than oligo(dC) greater than oligo(dA) greater than or equal to oligo(dI)] and different ribonucleotide bases [poly(G) = poly(I) greater than poly(U) greater than poly(A) greater than or equal to poly(C)]. Quantitatively, Tam-Re bound significantly less to oligo(dT)-cellulose than did OH-Tam-Re, which did not differ significantly from E2-Re, a result probably related to the dissociation of the lower affinity ligand from the Re/oligo(dT)-cellulose during the assay procedure. Unoccupied Re also bound selectively to these synthetic polynucleotides. It is concluded that: 1) selective binding of Re to synthetic polynucleotides is inhibited by 10 mM sodium molybdate; 2) estradiol is not essential for selective binding to synthetic polynucleotides, since unoccupied Re was only slightly less efficiently bound than E2-Re; and 3) selective binding of Re to synthetic polynucleotides was unaffected by the agonist or antagonist properties of the ligand bound at the steroid-binding site. These data suggest that nonsteroidal antiestrogens are unlikely to exert their antagonist activity by modulating the function of the polynucleotide-binding site of Re.

Animals↗
PubMed1984

Disparate effects of triphenylethylene antiestrogens on estrogen and progestin biosyntheses by cultured rat granulosa cells.

The influence of triphenylethylene antiestrogens on FSH-stimulated production of estrogen, progesterone, and 20 alpha-hydroxy-4-pregnen-3-one (20 alpha-OH-P) was examined in cultured rat granulosa cells. The cells were cultured with increasing concentrations of FSH, with or without diethylstilbestrol (DES) or various antiestrogens. After 3 days, medium progesterone and 20 alpha-OH-P contents were determined. Cells were reincubated for an additional 8 h with delta 4-androstene-3,17-dione, and estrogen formation was measured. Steroid production was negligible by cultures treated with DES or antiestrogens alone. FSH treatment increased estrogen and progestin production, while the addition of DES (10(-7) M) further enhanced FSH-stimulated steroidogenesis. Likewise, treatment with 10(-6) M of the antiestrogens tamoxifen (Tam), nafoxidine (Naf), or clomiphene citrate (CC) also enhanced FSH-stimulated aromatase activity. In contrast, the antiestrogens each inhibited FSH stimulation of progesterone and 20 alpha-OH-P production (greater than 73% inhibition at 300 ng/ml FSH). Increasing concentrations (3 X 10(-8)-10(-6) M) of the antiestrogens augmented the stimulatory effect of FSH (10 ng/ml) on estrogen production in a dose-related manner (CC greater than Tam greater than Naf). Similar doses of these antiestrogens inhibited the stimulatory effect of FSH (300 ng/ml) on progesterone and 20 alpha-OH-P production (Tam greater than CC greater than Naf). The observed inhibition of progestin production is associated with decreases in FSH-stimulated pregnenolone biosynthesis in antiestrogen-treated cells incubated with 10(-6) M cyanoketone. Furthermore, the antiestrogens inhibited the binding of [3H]estradiol to ovarian estrogen receptors with binding affinity constants of 364, 437, and 2144 nM for CC, Tam, and Naf, respectively. Thus, antiestrogens exert disparate actions on granulosa cell estrogen and progestin biosyntheses. Like estrogens, CC, Tam, and Naf enhance FSH-stimulated aromatase activity with potencies comparable with their abilities to interact with ovarian estrogen receptors. However, unlike estrogens, the antiestrogens inhibit FSH-stimulated progestin biosynthesis, partially via suppression of pregnenolone biosynthesis. The present granulosa cell culture system provides a valuable model for elucidating the disparate actions of estrogens and antiestrogens on ovarian steroidogenesis.

Animals↗
PubMed1996

Relationships among sex steroids, oxytocin, and their receptors in the rat uterus during late gestation and at parturition.

Sex steroids and oxytocin (OT) produced within intrauterine tissues have been implicated in the regulation of parturition. The purpose of these studies was 1) to determine the relationships among estradiol (E2), progesterone (P4), OT, and their receptors in uterine tissues during late gestation and parturition in the rat; 2) to observe the effects of the estrogen antagonist tamoxifen (TAM) on these factors; and 3) to evaluate the rat as a potential model for events at human parturition. Concentrations of E2, P4, PGE2, and OT were measured by RIA. E2 receptor (ER) was measured by enzyme immunoassay, and P4 receptor (PR) and OT receptor (OTR) were measured by binding assays. OT messenger RNA (mRNA) was measured by ribonuclease protection assay. Groups (n = 5) of pregnant rats (normal gestation = 22 days) were treated with TAM (200 mg/day) or vehicle and killed on gestation day 19, 21, 21.5, or 22 or after delivery of the first pup. Serum E2 increased throughout late gestation accompanied by an increase in uterine OT mRNA and ER. Serum P4 declined after day 19, and uterine PR did not change significantly. Uterine PGE2 increased progressively, reaching peak levels the evening before delivery. Uterine OTR did not increase until the morning of delivery, and uterine OT peptide concentrations increased only during parturition. Parturition was significantly delayed by 24 h in the TAM-treated group. TAM inhibited the increase in serum E2, uterine ER, and OT mRNA and peptide, but had no effect on serum P4 or uterine PR levels. With TAM, the responses of uterine OTR and PGE2 were significantly delayed, but still underwent a significant increase before the delayed parturition. These results support the hypothesis that E2 stimulates the synthesis of ER, OT, and OTR within the rat uterus and is essential for normal parturition. P4 withdrawal may be more important to the increases in OTR and PGE2, but these are delayed in the absence of estrogen. These data also suggest that the rat may be a relevant model for human parturition.

Animals↗
PubMed1993

Presence of a specific antiestrogen binding site on human follicular thyroid carcinoma cell line (UCLA RO 82 W-1): inhibition by an endogenous ligand present in human serum.

A receptor for antiestrogens, distinct from the estrogen receptor, has been identified in several tissues including the MCF-7 breast cancer cell line. Estrogen receptors have also been found in normal and pathological thyroid tissue homogenates. We demonstrate the presence of an antiestrogen binding site (AEBS) on a pure human follicular thyroid carcinoma cell line (UCLA RO 82 W-1) using a 3H-tamoxifen (3H-TAM) binding assay. The binding of 3H-TAM to the AEBS was determined after preincubation (30 min) of the cells with excess 17 beta-estradiol (2 mumol/L). Specific and saturable binding of 3H-TAM to the cells was observed. Displacement of the tracer from its binding site was dose dependent. Scatchard analysis revealed a dissociation constant (Kd) of 73 nmol/L, indicating a binding site with moderate affinity and capacity (72 pmol/10(6) cells). Using this assay we were also able to demonstrate the presence of an endogenous ligand for the AEBS in ethanol extracts of human serum. Cell growth and 3H-thymidine incorporation by the follicular thyroid carcinoma cells were inhibited when the cells were exposed to TAM (1.5 mumol/L). In conclusion, TAM is able to bind to a specific receptor on this follicular thyroid carcinoma cell line, and a natural circulating ligand present in ethanol extracts of human serum interferes with its binding.

Adenocarcinoma, Follicular↗
PubMed1991

Antitumor effects of droloxifene, a new antiestrogen drug, against 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats.

The antitumor effects of droloxifene (DROL, (E)-alpha-[p-[2-(dimethylamino)ethoxy]-phenyl]-alpha-ethyl-3-stilbeno l), a new antiestrogen drug, on 7,12-dimethylbenz(a)anthracene (DMBA)-induced estrogen-dependent mammary tumors in rats were studied and compared with those of tamoxifen (TAM). Mammary tumors appeared from about 2 months after p.o. administration of DMBA to female rats, and all of them were estrogen receptor (ER) and progesterone receptor positive. DROL and TAM (p.o.) inhibited the growth of the tumors. Both drugs inhibited the binding of 125I-estradiol-17 beta to ER in the cytosol of the tumor in vitro, and the effect of DROL was much stronger than that of TAM. When 3H-estradiol-17 beta (3H-E2) was given s.c. to rats with the mammary tumors, 3H-E2 accumulated in the tumors, uteri and vaginae in which the ER levels are known to be high, but was low in the heart, in which the ER levels are normally low. DROL and TAM decreased the levels of 3H-E2 in the tumors, uteri and vaginae, but had no effect in the hearts. When DROL or TAM was given p.o. to rats daily for 7 consecutive days after administration of DMBA, they inhibited the induction of mammary tumors by DMBA. From these results, DROL inhibits the growth and the initiation of DMBA-induced mammary tumors by inhibiting the binding of estrogen to its receptor.

9,10-Dimethyl-1,2-benzanthracene↗