Inhibition of estradiol binding to its receptor by the cupric ion

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Serum osteocalcin (BGP) in tumor-associated hypercalcemia

Serum osteocalcin (BGP) is a new marker of bone turnover that reportedly evaluates bone formation. Thus, its measurement could assess the bone formation rate in tumor-associated hypercalcemia. We measured concentrations of BGP and other parameters of bone metabolism in 54 untreated hypercalcemic cancer patients as compared to 109 healthy subjects. Primary tumor sites were breast (19), lung (11), head and neck (6), multiple myeloma (3), kidney (2), and various (11) or multiple (2). Mean BGP levels were higher in the hypercalcemic subjects, 4.6 ± 0.4 (SEM) ng/ml, than in the normal subjects, 3.6 + 0.1 ng/ml (p < .05), and were normalized in the 22 patients who could be reevaluated after successful treatment of hypercalcemia with intravenous aminohydroxypropylidene diphosphonate (APD). There was no correlation of BGP levels with age, sex, or renal function. Compared with the Gaussian distribution in the normal subjects, there was a considerable scatter of the data in hypercalcemic patients, suggesting the existence of defined subgroups with abnormally low or abnormally high values. However, we found no significant relationship of BGP concentrations with tumor site or histology or with bone metastatic involvement. We found also no significant correlation between concentrations of serum BGP and total or ionized calcium, alkaline phosphatase, parameters of bone resorption, and indices of parathyroid function. In summary, serum BGP levels were slightly elevated in tumor-associated hypercalcemia and were normalized after successful treatment of hypercalcemia. More importantly, BGP concentrations varied widely even in the subgroups of patients with hypercalcemia accompanying massive bone metastatic involvement or in the patients without detectable skeletal metastases. Thus, BGP determination cannot help to differentiate between paraneoplastic hypercalcemia and hypercalcemia due to metastatic bone lysis; moreover, our findings suggest great variability of the bone formation rate in tumor-associated hypercalcemia, whether bone metastases are present or not.SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Treatment of malignancy-associated hypercalcemia with intravenous aminohydroxypropylidene diphosphonate

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Circulating PTHrP concentrations in tumor-induced hypercalcemia: Influence on the response to bisphosphonate and changes after therapy

We studied the influence of circulating parathyroid hormone-related protein (PTHrP) concentrations on the response of hypercalcemic cancer patients to bisphosphonate therapy. We also examined the changes in circulating PTHrP levels during the normalization of serum Ca to determine if part of the increase in PTHrP concentrations is not secondary to hypercalcemia itself, as suggested by some in vitro data. We sequentially measured in 45 hypercalcemic cancer patients treated by pamidronate the circulating concentrations of PTHrP (by an amino-terminal RIA; normal values <9 pmol/liter), Ca, Ca2+, Pi, intact PTH, and the fasting urinary excretion of Ca (Ca/Cr) and cyclic AMP (cAMP). Mean ± SEM baseline PTHrP levels were 9.5 ± 1.3, with a median (range) value of 6.0 (< 3.4–43) pmol/liter. PTHrP levels were elevated in 18 of 45 patients, more often in epidermoid than in glandular carcinomas (P < 0.05), and they were significantly (P < 0.05) correlated with the concentrations of Pi (r = -0.46), Ca/Cr (r = -0.31), and urinary cAMP (r = 0.47). Mean pretreatment Ca levels were not significantly different between patients with elevated and patients with normal PTHrP levels, 13.3 ± 0.4 versus 12.9 ± 0.4 mg/dl, but the concentrations became significantly different (P < 0.005) 4 days after therapy, 10.2 ± 0.3 versus 9.2 ± 0.1 mg/dl, respectively. The fall in fasting urinary Ca excretion was significantly (P < 0.05 from day 4 to day 14) lower in patients with elevated baseline PTHrP levels: for example, Δ (day 4 - day 0), 0.31 ± 0.11 in patients with elevated PTHrP levels versus 0.64 ± 0.08 mg Ca per mg Cr in patients with normal PTHrP levels. In agreement with a lesser effect on serum Ca, intact PTH levels did not increase significantly in patients with elevated PTHrP levels, in contrast with a clear-cut recovery of PTH secretion in the other group. Last, PTHrP levels did not change significantly after bisphosphonate therapy: for example, at the day of the nadir of Ca, the levels were 8.2 ± 1.2 (6.4, < 3.4–28) pmol/liter. In summary, our data suggest that circulating PTHrP concentrations do not change during correction of tumor-induced hypercalcemia but significantly influence the response to bisphosphonate therapy. Elevated PTHrP concentrations in hypercalcemic cancer patients thus constitute a primary phenomenon of pathogenic importance.SCOPUS: ar.jFLWNAinfo:eu-repo/semantics/publishe

Protein synthesis is not implicated in the ligand-dependent activation of the estrogen receptor MCF-7 cells

In MCF-7 cells, estrogen receptor (ER) elimination occurs rapidly under stimulation with estradiol (E2) at 1 NM ('ER processing'); cycloheximide (CHX) at 50 μM impedes this phenomenon. ER processing is also observed when E2 is removed after the first hour of incubation, indicating that the role of the hormone would be limited to the initiation of this process. When CHX is removed at the same time, receptor processing and, later, the induction of progesterone receptor (PgR) both proceed. The initial estrogenic signal which activates ER is therefore not influenced by CHX. In support of this conclusion, no effect of the drug on E2 binding affinity of residual ER was detected. A similar result was recorded for a series of estrogens and antiestrogens, indicating that CHX exerts no influence on the potential agonistic/antagonistic potency of any ligand. Size-exclusion chromatography (FPLC) revealed that [3H]E2-induced ER activation leads to the cleavage of the native receptor (67 kDa) into low molecular weight isoforms which subsequently become less detectable over time (proteolysis). In the presence of CHX, such ER isoforms persist, confirming the absence of interference of the drug with the activation step. When the cells were prelabelled with [3H]tamoxifen aziridine ([3H]TAZ before their exposure to E2, ER cleavage could not be detected due to the lack of activation potency of the antiestrogen ligand. However, the [3H]TAZ-ER complexes were subjected to E2-induced processing; CHX blocked this phenomenon, which is associated with the maintenance of ER synthesis and activation.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Recovery of parathyroid hormone secretion during correction of tumor- associated hypercalcemia

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Absence d'implication des récepteurs d'œstrogènes dans les phénomènes de toxicité ovarienne induits par les psoralènes

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Molecular basis of agonistic activity of ERa17p, a synthetic peptide corresponding to a sequence located at the N-terminal part of the estrogen receptor a ligand binding domain

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Fluorous tolerance of the estrogen receptor alpha as probed by 11-polyfluoroalkylestradiol derivatives

The concern of this work was to try to delineate factors, inherent to fluorination, susceptible to influence estradiol binding to the estrogen receptor alpha (ERα). For this purpose, fluorinated chains were linked at 11β position of the steroid (i.e. C6F13, CH2CH2C4F9, CH2CH2C8F17). Relative binding affinity (RBA) for ERα of these compounds and of other related fluorinated derivatives was compared to those of non-fluorinated analogs. Despite being relatively well accepted by the receptor, investigated compounds exhibited lower RBA values at 0 °C than their non-fluorinated counterparts. Nevertheless, heavily fluorinated chains were tolerated in so far as they are not too long (C-4) and insulated from the steroidal core by a two methylene spacer unit. Increase of the temperature of our binding assay (25 °C) failed to change the RBA values of two selected polyfluorohexyl derivatives while it drastically enhanced the value of the corresponding non-fluorinated analogs. Rigidity of the chain induced by fluorination as well as the oleophilic (fluorophobic) nature of the estradiol binding cavity of ERα is proposed to explain these properties. © 2007 Elsevier Inc. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Molecular basis of agonistic activity of ERα17p, a synthetic peptide corresponding to a sequence located at the N-terminal part of the estrogen receptor α ligand binding domain

SCOPUS: ar.jinfo:eu-repo/semantics/publishe