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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of novel gonadotropin releasing hormone (GnRH) and Somatostatin analogs have been developed in our laboratory and were screened for antiproliferative and signal transduction inhibitory effect. Our GnRH analog Folligen, had significant antitumor activity on DMBA induced mammary carcinomas in rats without blocking ovarian functions. The direct effect of Folligen and Buserelin has been compared on the human breast cancer cell line MDA-MB-231. Folligen was found to be more effective in inhibiting cell proliferation and significant differences were found in the signal transduction pathways activated by these analogs. Our novel Somatostatin analogs were screened for tyrosine kinase inhibition and for antiproliferative effect on human colon tumor cells and for growth hormone (GH) release inhibition in vitro and in vivo. The analog TT-2-50 was significantly more active inhibiting GH release in superfused rat pituitary cells and in vivo than native Somatostatin and it strongly inhibited tyrosine kinase and proliferation while it stimulated protein kinase C activity.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Novel antitumor peptide hormones and their effect on signal transduction. 135 11

NADPH cytochrome c (P-450) reductase was purified from human placental microsomes using a combination of affinity and gel filtration chromatography. Affinity chromatography using agarose-hexane-adenosine 2'5 diphosphate resulted in two protein bands being detected by SDS-PAGE of approximate MwS 68 and 75 kDa. Fractions containing the two proteins were pooled, and then resolved using Sephacryl S-200. Both of the purified proteins displayed enzyme activity, measured by their ability to reduce cytochrome c. The 75 kDa protein obtained was used to immunize three female New Zealand white rabbits. The IgG fraction was partly purified from rabbit sera which suppressed placental microsomal NADPH cytochrome c reductase activity by > 80% using 33% ammonium sulphate. The procured antibody suppressed androstenedione aromatase activity in microsomal preparations of human placental and breast adipose tissue, and NADPH cytochrome c reductase activity in prostate (benign and malignant), MDA-MB-231 breast cancer cells, breast adipose, Hep G2 hepatoma cells and placental microsomal preparations. The extent of NADPH cytochrome c reductase inhibition varied in the order of malignant prostate < benign prostate < MDA < breast adipose < Hep G2 < placenta. The results suggest that human placental NADPH cytochrome c (P-450) reductase shares common antigenic epitopes pertinent to its capability of reducing cytochrome c in all of the above-mentioned tissues. In attempting to associate possible changes in NADPH cytochrome c reductase activity imposed by neoplasia to the obtained immunochemical cross reactivity and enzyme activity results, it was noted that microsomes obtained from MDA cells exhibited enzyme activity significantly less than that of breast adipose microsomes (1.6 and 8.1 nmol/min/mg protein, respectively) and by comparison showed 6% less homology towards the placental antibody. The results obtained for benign and malignant prostate showed no significant difference between the neoplastic states as adjudged by enzyme activity and immunochemical assays.
J Steroid Biochem Mol Biol 1992 Nov
PMID:Immunochemical specificity of placental NADPH cytochrome c (P-450) reductase in neoplastic and non-neoplastic human tissue. 141 86

Concentration of MDA in isolated control, ischemic, and reperfused rat hearts was determined by using a new sensitive and reproducible HPLC method on the perchloric acid extract of the freeze-clamped tissues. By means of this HPLC assay for the direct measurements of MDA, concentrations of adenine nucleotide derivatives were also obtained in the same chromatographic run. Under the present experimental conditions, no detectable amount of MDA could be observed in control hearts while ischemic hearts showed 0.009 mumoles/g d.w. of MDA (s.d. = 0.001), this value representing the sensitivity limit of the method employed. On the contrary, reperfused hearts showed 0.118 mumoles/d d.w. of MDA (s.d. = 0.036), thereby indicating that this compound originates from an oxygen free radical-mediated breakdown of phospholipids and demonstrating the existence of quantifiable molecular damage occurring upon reperfusion. On the whole, our data demonstrate that MDA, if properly assayed, is a reliable index of peroxidative injury to biological systems.
Mol Cell Biochem 1992 Oct 21
PMID:Malondialdehyde is a biochemical marker of peroxidative damage in the isolated reperfused rat heart. 148 Jan 49

The antiestrogen tamoxifen is used in the treatment of hormone-responsive breast cancer. However, therapeutic failure has frequently been observed in both patients and animal models after long term treatment. We have studied the effect of a point mutation that leads to the substitution of Val for Gly at codon 400 in the ligand-binding domain of the estrogen receptor (ER) on estrogenic and antiestrogenic activities of 4-hydroxytamoxifen (4-OHT) and its derivatives. Stable ER transfectants derived from MDA-MB-231 CL10A, an ER-negative breast cancer cell line, have been used in these studies. 4-OHT and its fixed ring derivatives showed more estrogen-like activity in ER transfectants than in MCF-7, an ER-positive breast cancer cell line. In this study, 4-OHT was a partial agonist of cell growth in the transfectant S30 cells, which express the wild-type ER. However, it was a full agonist in the mutant ER transfectant ML alpha 2H, which expressed ER with Val at codon 400. The increased estrogenic activity of 4-OHT in ML alpha 2H cells was not due to the preferential isomerization of trans 4-OHT to cis 4-OHT, since the nonisomerizable fixed ring trans 4-OHT was a partial agonist for cell growth in S30 cells and was a full agonist in ML alpha 2H cells. Transient transfection using a reporter plasmid containing an estrogen response element demonstrated that fixed ring trans 4-OHT had estrogenic activity in ML alpha 2H cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1992 Dec
PMID:Point mutation of estrogen receptor (ER) in the ligand-binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing complementary DNAs for ER. 149 96

We investigated binding characteristics of basic fibroblast growth factor (bFGF) on membranes prepared from 4 human breast cancer cell lines and 38 primary BC biopsies. Competitive binding experiments were performed and analyzed using the "Ligand" program. Furthermore bFGF mitogenic activity was measured by [3H]thymidine incorporation into DNA from breast cancer cell lines. The presence of high-affinity binding sites was demonstrated in each cell type (MCF-7: Kd = 0.60 nM; T-47D: Kd = 0.55 nM; BT-20: Kd = 0.77 nM; MDA-MB-231: Kd = 0.34 nM). The presence of these high-affinity binding sites was confirmed with saturation experiments. A second class of low-affinity binding sites was detected in the 2 hormone-independent cells (BT-20: Kd = 2.9 nM; MDA-MB-231: Kd = 2.7 nM). bFGF stimulated the proliferation of MCF-7, T-47D, BT-20 but not MDA-MB-231 cell lines. With competition experiments, binding sites were detectable in 36/38 breast cancers; high-affinity binding sites (Kd less than 1 nM) were present in 19/36 cases and low-affinity binding sites (Kd greater than 2 nM) were present in 29/36 cases (the two classes of binding sites were present in 12 breast cancers). No relation between bFGF binding sites and node involvement, histologic type or grading of the tumor was evidenced. There were negative correlations (Spearman test) between total bFGF binding sites and estradiol receptor (P = 0.05) or progesterone receptor (P = 0.009). The demonstration of (1) bFGF specific binding sites in breast cancer membranes, and (2) bFGF growth stimulation of some breast cancer cell lines indicates that this factor may be involved directly in the growth of some breast cancers.
J Steroid Biochem Mol Biol 1992 Sep
PMID:Basic fibroblast growth factor (bFGF): mitogenic activity and binding sites in human breast cancer. 152 70

Currently there is much interest in the role that growth factors may play in the development of human breast tumours. We have shown previously that growth factors secreted by breast tumours may influence the activity of oestradiol hydroxysteroid dehydrogenase, the enzyme which catalyses the interconversion of oestrone (E1) and oestradiol. As the formation of E1 from its sulphate (E1S) by oestrone sulphatase may be quantitatively more important than production from androstenedione via aromatase, we have studied the effect of insulin-like growth factor-1 (IGF-I) and basic fibroblast growth factor (bFGF) on oestrone sulphatase activity in the hormone-dependent MCF-7 and the hormone-independent MDA-MB-231 breast cancer cell lines. In both these cell types, bFGF (1-200 ng/ml) and IGF-I (25-200 ng/ml) significantly stimulated oestrone sulphatase activity in a dose-dependent manner (by 8-60%) after 48 h. Additionally, cycloheximide significantly inhibited (by 90-120%) this stimulation of oestrone sulphatase activity by the two growth factors in both MCF-7 and MDA-MB-231 cells. Basal oestrone sulphatase activity was higher in the oestrogen receptor, ER-ve MDA-MB-231 cells than in the ER + ve MCF-7 breast cancer cells. We conclude that these growth factors, believed to be secreted by breast tumours, may induce enzymes of oestrogen synthesis and hence increase local production of oestrogens.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Modulation of oestrone sulphatase activity in breast cancer cell lines by growth factors. 156 28

Of the total number of breast cancers approx. 30-50% are hormone-dependent and estradiol is one of the main factors of cancerization. Consequently, the control of this hormone inside the cancer cell is of capital importance because it is well established that the inhibition of estradiol biosynthesis can have a positive effect on the evolution of the disease. The blockage of estradiol can be obtained by the action of anti-aromatases, anti-sulfatases, the control of the 17 beta-hydroxysteroid dehydrogenase activity or by the stimulation of the sulfotransferase which converted the estrogens in their sulfates. In breast cancer tissue estrone sulfate is quantitatively the most important source of estradiol. In the intact cell, estrone sulfatase activity is very intense in the hormone-dependent cell lines (e.g. MCF-7, T-47D) but very small activity is observed in the hormone-independent (e.g. MDA-MB-231, MDA-MB-436) cell lines. However, this activity became very strong after homogenization in the hormone-independent cells, suggesting the presence of repressive factor(s) for this enzyme or its sequestering in an inactive form, in the intact cells of these cell lines. In a series of previous studies it was found that in hormone-dependent cell lines different anti-estrogens: tamoxifen and derivatives, ICI 164,384, very significantly decrease the estradiol concentration originated from estrone sulfate, and recently it was observed that Decapeptyl (D-Trp6-gonadotropin-releasing hormone) in the presence of heparin can also decrease the conversion of estrone sulfate into estradiol. No significant effect was obtained in the presence of heparin or Decapeptyl alone. The estrone sulfatase activity can be inhibited by progesterone, the progestagen R-5020, and testosterone. In another series of recent studies the presence of very strong estrogen sulfotransferase activity has been shown in one breast cancer cell line, the MDA-MB-468. We can conclude that: (1) the control of estradiol concentration can be carried out in the breast cancer tissue itself; (2) estrone sulfate can play an important role in the bioavailability of estradiol in the breast cancer cell; and (3) as is the case for the aromatase, the control of: the estrogen sulfatase, estrogen sulfotransferase, and 17 beta-hydroxysteroid dehydrogenase can be new targets for therapeutic applications in breast cancer.
J Steroid Biochem Mol Biol 1992 Mar
PMID:Recent data on estrogen sulfatases and sulfotransferases activities in human breast cancer. 158 Sep 21

Exhaustive endurance exercise in adult female albino rats (C-Ex) increased the generation of free radicals (R.) in the myocardium, probably through enhanced oxidative mechanisms. Free radical mediated lipid peroxidation measured in the form of tissue MDA content also increased in C-Ex animals, suggesting the exercise-induced oxidative stress in these animals. Dietary supplementation of Vit E, for a period of 60 days significantly increased Vit E incorporation into the serum and myocardium, more so in the myocardium. Vit E supplementation to exercising animals completely abolished the radical production. The protection of Vit E against oxidative stress appears to be not mediated through the improvement of antioxidant mechanisms by enzymes like SOD, catalase and Se-GSH Px. However the non Se-GSH Px, the enzyme involved in the reduction of endoperoxides increased significantly in control and Vit E fed animals in response to exercise. The protection of Vit E against exercise-induced oxidative stress was correlated with its multivarious activities like a) scavenger of free radicals; b) inhibition of lipoxygenases; and c) reduction of peroxides in association with lipoxygenases. These studies indicate that dietary supplementation of Vit E protects the animals from the possible oxidative damages of endurance exercise.
Mol Cell Biochem 1992 Apr
PMID:Dietary supplementation of vitamin E protects heart tissue from exercise-induced oxidant stress. 158 32

Estradiol-17 beta (E2) is converted exclusively to intracellular metabolites, termed lipoidal estrogens [long chain fatty acid 17 beta-esters (E2-L)], by human mammary cancer tissue and cell lines. In order to further evaluate the biological role of lipoidal estrogens, rates of saturation of the estrogen receptor (ER) along with formation of [3H]E2-L have been measured in human mammary cancer cells exposed to 5 nM [3H]E2. Extensive specific binding of E2 to ER in MCF-7 cells (approximately 37%) and ZR-75-1 cells (approximately 62%) occurred before appreciable synthesis of E2-L was evident and the maximum level of E2-L attained was only 3-9% of the E2 specifically bound to ER. In these ER positive cell lines, and in the ER negative cell line MDA-MB-231, an initial rise in the rate of E2-L formation was followed by a decrease at approximately 6 min and re-establishment of a new rate, indicating turnover of the E2-L fraction by esterification-de-esterification reactions. This data does not support the concept that E2-L acts in the transport of E2 to nuclear receptors, but rather than liberation of E2 from E2-L could serve to maintain occupancy of ER necessary for initiation of DNA synthesis. The esterase, as studied in pooled human mammary cancer tissue, was found to hydrolyse E2-17 beta-long chain fatty acid esters at different rates--the enzyme being less active towards E2-17 beta-stearate compared to E2-17 beta-oleate, -linoleate and -linolenate. Esterase activity was significantly higher in MDA-MB-231 cells compared to MCF-7 cells. Treatment of MCF-7 cells with E2 did not alter the specific activity of the esterase towards E2-17 beta-oleate as substrate. Similarly, addition of dibutyryl c-AMP to ZR-75-1 cell cultures was without effect on E2-L, both during the time when E2-L was accumulating, or during a subsequent phase when E2-L was decreasing following transfer to medium lacking E2. Calcitonin, which increases endogenous c-AMP in MCF-7 cells, had no effect on E2-L in this latter phase using this cell line. Thus, no evidence could be provided that the esterase was under E2 control, or control by polypeptide hormones which utilize c-AMP as a second messenger.
J Steroid Biochem Mol Biol 1991 Nov
PMID:Metabolism of lipoidal derivatives of estradiol-17-beta in human mammary cancer tissue and cell lines. 165 70

Monoclonal antibody (MAb) 4D5 was used to analyze the phosphorylation of p185HER2, the gene product of c-erbB-2/HER2, in SK-BR-3 cells. Culture in the continuous presence of 4D5 reduced the in vivo steady-state levels of p185HER2 phosphorylation by 80% in a dose-dependent manner, suggesting that MAb 4D5 may have interfered with the activation of phosphorylation of p185HER2. The observed MAb-mediated reduction of p185HER2 phosphorylation could not be completely accounted for by down-regulation. When cultures were grown under serum-free conditions, the steady-state levels of p185HER2 phosphorylation were reduced by 56%, and addition of 4D5 further inhibited phosphorylation to 20% of steady-state levels. With continuous exposure to increasing concentrations of newborn calf serum in these cultures, there was a linear increase in tyrosine-specific phosphorylation of p185HER2, reaching a 5.4-fold increase with 10% newborn calf serum. Phosphorylation of p185HER2 in the presence of newborn calf serum was not attributable to stimulation of the epidermal growth factor receptor by epidermal growth factor or by transforming growth factor-alpha. Extension of these observations to two other mammary carcinoma cell lines. MDA-MB-453 and BT-474, also demonstrated a significant capacity of serum to induce p185HER2 phosphorylation. The demonstration of antibody-mediated partial inhibition of phosphorylation under serum-free conditions suggests that mammary carcinoma cells may also produce and secrete a factor or factors which may activate p185HER2. Our observation that growth-inhibitory MAb 4D5 is able to reduce the phosphorylation of p185HER2 by newborn calf serum and by a cellular-derived factor(s) suggests the existence of a growth factor(s) which uses phosphorylation of p185HER2 as a signal transduction pathway to regulate cell proliferation.
Mol Cell Biol 1991 Feb
PMID:Regulation of phosphorylation of the c-erbB-2/HER2 gene product by a monoclonal antibody and serum growth factor(s) in human mammary carcinoma cells. 167 Dec 97


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