RESUMEN
Treatment of malignancy-associated hypercalcemia remains unsatisfactory. We have prospectively treated 26 consecutive hypercalcemic cancer patients with intravenous (IV) aminohydroxypropylidene diphosphonate (APD). The drug was administered daily as a 15-mg two-hour IV infusion until both serum and urinary calcium had been normalized for 48 hours. Twenty-four patients were fully evaluable (eight head and neck tumors, seven breast cancers, three epidermoid tumors of the lung, and six miscellaneous neoplasms). Whereas rehydration had only inconsistent effects, APD normalized serum calcium in all patients after a mean of three daily doses: serum calcium decreased from 13.3 +/- 0.4 mg/dL (mean +/- SEM) before APD to 8.0 +/- 0.1 mg/dL at the end of treatment. Ionized calcium declined in parallel to total calcium. APD was as effective in hypercalcemia due to bone metastases as in paraneoplastic hypercalcemia. The drug was tolerated without toxicity and had a prolonged effect: serum calcium remained normal during 3+ weeks (1 + to 8 +) in 17 patients who did not receive or did not respond to antitumoral treatment. APD normalized serum calcium by inhibiting bone resorption, as evidenced by the dramatic decrease in urinary excretion of calcium and hydroxyproline. Inhibition of bone resorption was probably also responsible for the decrease in serum phosphorus from 2.9 +/- 0.2 to 2.0 +/- 0.1 mg/dL. In summary, IV APD constitutes a major advance in the treatment of malignancy-associated hypercalcemia: it is very effective, well tolerated, and has a prolonged efficacy.
Asunto(s)
Difosfonatos/uso terapéutico , Hipercalcemia/prevención & control , Adulto , Anciano , Neoplasias Óseas/secundario , Neoplasias de la Mama/metabolismo , Calcio/sangre , Calcio/orina , AMP Cíclico/orina , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Hidroxiprolina/orina , Hipercalcemia/sangre , Hipercalcemia/orina , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Osteólisis/prevención & control , Pamidronato , Fósforo/sangreRESUMEN
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 less than .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.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Huesos/metabolismo , Proteínas de Unión al Calcio/sangre , Hipercalcemia/sangre , Neoplasias/complicaciones , Anciano , Biomarcadores/sangre , Femenino , Humanos , Hipercalcemia/etiología , Hipercalcemia/orina , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/orina , OsteocalcinaRESUMEN
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Difosfonatos/uso terapéutico , Hipercalcemia/sangre , Neoplasias/complicaciones , Hormona Paratiroidea/sangre , Proteínas/fisiología , Adulto , Anciano , Calcio/sangre , Femenino , Humanos , Hipercalcemia/tratamiento farmacológico , Hipercalcemia/etiología , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Pamidronato , Hormona Paratiroidea/fisiología , Proteína Relacionada con la Hormona Paratiroidea , Proteínas/metabolismoRESUMEN
Spontaneous recovery of parathyroid secretion during correction of tumor-associated hypercalcemia by bisphosphonates provides a unique clinical opportunity to further unravel the complex relationship between Ca and PTH levels. We measured plasma ionised Ca (Ca2+) and serum intact PTH concentrations in 31 hypercalcemic cancer patients every 2 (range, 1-3) days over a period of 3-21 (median, 7) days after pamidronate therapy. The mean (+/- SD) initial Ca2+ concentration was 1.64 +/- 0.20 mmol/L (normal, 1.05-1.26 mmol/L), with a corresponding PTH level of 4.9 +/- 2.6 (median, 4.5; range, less than 2.0-14.7) ng/L. PTH levels were subnormal in 30 of 31 patients. During correction of hypercalcemia, the relationship between Ca2+ and PTH concentrations was best described by a polynomial regression (r = 0.89; P less than 0.001). The curve of the regression entered the normal range of PTH levels (10.5 ng/L) for a Ca2+ concentration of 1.21 mmol/L. Similarly, the mean Ca2+ level that caused a reproducible increase in PTH levels compared to baseline values was 1.21 +/- 0.12 (median, 1.17; range, 1.00-1.45) mmol/L. Comparable values were obtained when day to day variations in PTH levels were considered; the mean Ca2+ threshold level was 1.24 +/- 0.12 (median, 1.25; range, 1.00-1.43) mmol/L. This PTH secretory threshold was not significantly influenced by several factors, including the type of cancer hypercalcemia, the day to day variations in Ca2+ levels, various biochemical parameters of calcium metabolism, or the number of days to obtain a normal Ca2+ concentration. In summary, contrary to previous reports, our data show that the PTH secretory threshold during correction of tumor-associated hypercalcemia lies in the upper part of the normal range of Ca2+ concentrations and is not significantly influenced by the rate of change in Ca2+ levels.
Asunto(s)
Difosfonatos/uso terapéutico , Hipercalcemia/sangre , Neoplasias/fisiopatología , Hormona Paratiroidea/metabolismo , Calcio/sangre , Femenino , Humanos , Hipercalcemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pamidronato , Hormona Paratiroidea/sangre , Valores de Referencia , Análisis de RegresiónRESUMEN
In MCF-7 cells, estrogen receptor (ER) elimination occurs rapidly under stimulation with estradiol (E2) at 1 nM ('ER processing'); cycloheximide (CHX) at 50 microM 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 antiestrogenic 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.
Asunto(s)
Cicloheximida/farmacología , Estradiol/farmacología , Inhibidores de la Síntesis de la Proteína/farmacología , Receptores de Estrógenos/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Estradiol/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Puromicina/farmacología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Carbetimer is a new antineoplastic agent whose limiting toxicity consists of dose- and treatment duration-dependent hypercalcemia. We examined the short-term effects of Carbetimer on calcium metabolism on days, 1, 3 and 5 during 11 5-day courses (6.5-8.2 g/m2/day given over daily 2-h infusions, q 3-4 weeks). Blood parameters were measured before and after Carbetimer, whereas urinary parameters were studied in three consecutive 2-h collections before, during and after Carbetimer infusions. Carbetimer effects were similar regardless of the infusion day. We found a consistent decrease of plasma ionized Ca (Ca2+) levels from 4.56 +/- 0.05 mg/dl before infusion to 4.28 +/- 0.06 mg/dl after infusion (P less than 0.001) whereas total serum Ca (corrected for protein levels) did not change. The fall of Ca2+ stimulated parathyroid function, as suggested by the increased plasma PTH levels, the decreased serum phosphorus and TmP/GFR index, or the increased urinary phosphate and cyclic AMP excretion. Carbetimer infusions also induced a marked increase in urinary Ca excretion (expressed as mg Ca/mg creatinine) from 0.093 +/- 0.011 before to 0.359 +/- 0.042 during and 0.177 +/- 0.031 after infusion (P less than 0.011). These changes were best explained by Carbetimer-induced Ca chelation that we confirmed in vitro by incubating Carbetimer at various concentrations in whole blood for 2 h at 37 degrees C, e.g. 2 mg of Carbetimer/ml lowered Ca2+ from 4.82 to 3.20 mg/dl without changing total Ca levels. On the other hand, a direct effect of Carbetimer on bone cannot be excluded since we observed an increase of serum osteocalcin levels from 2.0 +/- 0.3 to 2.5 +/- 0.4 ng/ml after infusion (P less than 0.001). In summary, the short-term effects of Carbetimer on calcium metabolism markedly differ from the long-term effects. They mainly consist of a dose-related calcium chelation leading to a decrease in Ca2+ levels, an increase in urinary Ca excretion and a stimulation of parathyroid function.