Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report 2 cases of true hypocalcemia (not caused by decreased binding proteins) associated with metastatic prostate cancer and review previously reported cases. Hypocalcemia is a common but frequently unrecognized complication of prostatic cancer. Estrogen therapy often is associated with the hypocalcemia, which may be asymptomatic. The hypocalcemia is always associated with osteoblastic metastases and usually it is associated with increased serum alkaline phosphatase activity, acid phosphatase activity and serum parathyroid hormone concentration. Serum concentrations of magnesium, phosphorus and vitamin D frequently are decreased. Patients are in a positive calcium balance. The osteoblastic metastases seem to act as a calcium sink, creating a "hungry tumor phenomenon". The role of estrogens may be to stop the resorption of normal bone resulting in lower serum calcium concentrations.
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PMID:Hypocalcemia associated with estrogen therapy for metastatic adenocarcinoma of the prostate. 317 54

Calcitonin obtained from eels (ell-CT) was given to 14 patients who had developed bony pains due to bone metastases of malignant tumors and who did not respond to 12 various analgesics. The patients consisted of 12 males and 2 females, with a mean age of sixty-five. Eel-CT (Elcitonin) was injected intramuscularly to each patient at a dose of 40 units twice daily. Other analgesics were assessed to be ineffective at the time of CT administration and they were not given consideration in the evaluation. For the assessment of drug effect, a pain score was prepared. Eel-CT was markedly effective in 3 patients, effective in 8 patients, and ineffective in 2 patients. Eel-CT had a better effect on prostatic cancer than any other cancer. The analgesic effect was observed in the first week of drug administration at around a total dose of 1,000 units. Although the pain tended to appear at regions on which the body weight was liable to rest, the analgesic effect was seen irrespective of the side of pain. Since serum calcium, phosphate, parathyroid hormone (PTH), CT levels and bone scintigrams between pre-and post-CT administration did not differ, the analgesic mode of action of CT is not supposed to be related to inhibition of bone absorption nor bone formation. The therapeutic effect hardly suggests any direct action of CT on the tumor.
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PMID:[Effect of calcitonin on body pains caused by bone metastases of urogenital cancer]. 667 46

57 patients with advanced prostate cancer and a failure of prior hormonal treatment were selected for a double-blind placebo-controlled trial, in which they were randomly allocated to receive either clodronate (C) or placebo concomitantly with the basic cancer treatment, estramustine phosphate (E) (560 mg daily). The treatment was started intravenously with 300 mg of C or placebo in 5 consecutive days, and thereafter maintained orally with 1600 mg of C or identical placebo daily for 3 months. Bone biopsies were taken at admission and at 3 months. Measurements of serum calcium, phosphate, alkaline phosphatase, prostate-specific antigen and creatinine were made at the time of both bone biopsies and at 1 month. Serum intact parathyroid hormone and vitamin D metabolites were measured at admission and at 3 months. Because of several discontinuations, the study groups at final analysis comprised 20 patients taking E + C and 19 patients taking E and placebo. Bone resorption, as judged by eroded surface and osteoclast number, was markedly increased especially in biopsies taken from tumour-involved bone. Treatments with E + C or E both induced a significant decrease in bone resorption, but were associated with the development of hypocalcaemia, secondary hypoparathyroidism, hypophosphataemia and severe impairment of mineralisation of newly formed bone, i.e. osteomalacia. Since the patients were not vitamin D deficient, we conclude that osteomalacia resulted from a relative deficiency of calcium and phosphate. The transiency of pain relief achieved with anti-resorptive agents in the treatment of bone metastases from prostate cancer may be due to the development of osteomalacia.
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PMID:The effect of clodronate on bone in metastatic prostate cancer. Histomorphometric report of a double-blind randomised placebo-controlled study. 791 32

Prostate carcinoma is one of the most common malignancies affecting males, resulting in a high rate of morbidity and mortality. This hormone-dependent malignancy is characteristically associated with a high incidence of osteoblastic skeletal lesions. However, osteolytic lesions invariably accompany blastic ones. In the current study, we assessed the role of parathyroid hormone-related peptide (PTHRP), a potent bone-resorbing agent, in contributing to bone breakdown and prostatic skeletal metastasis using a syngeneic rat prostate cancer model. The full-length cDNA encoding rat PTHRP was subcloned as a Hind III insert in the sense orientation into the mammalian expression vector pRc-CMV to generate the expression vector pRc-PTHRP-S. Both control and experimental plasmids were stably transfected into low PTHRP-producing Dunning R3227, Mat Ly Lu rat prostate cancer cells. Following antibiotic selection, monoclonal cell lines expressing the highest amount of PTHRP mRNA and immunoreactive PTHRP were selected as experimental tumor cells for further analysis. Increased PTHRP production by these cells had no significant effect in vitro on the invasive capacity of these cells. Control and experimental cells were inoculated s.c. into the right flank or by the intracardiac (i.c.) route into the left ventricle of inbred male Copenhagen rats. No skeletal metastases occurred after s.c. injection with either cells. In contrast, i.c. inoculation led to lumbar vertebra metastasis and consequent hind-limb paralysis. Furthermore, histological examination of skeletal metastases in experimental animals showed a marked increase in osteoclastic activity. Our results demonstrate that PTHRP can increase osteoclastic osteolysis in the presence of focal osseous prostate cancer metastases and may contribute to the lytic lesions which generally accompany osteoblastic lesions in prostate cancer.
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PMID:Over-production of parathyroid hormone-related peptide results in increased osteolytic skeletal metastasis by prostate cancer cells in vivo. 993 8

Parathyroid hormone-related protein (PTHrP) is produced by prostate carcinoma cells and tumors, but little is known of its role in prostate carcinogenesis. The goal of this study was to evaluate PTHrP expression in the regulation of prostate carcinoma growth using human and animal models. PTHrP expression was assessed in prostate cancer cell lines in vitro. Seven of nine cell lines produced PTHrP, and increased expression was seen during cell proliferation. The MatLyLu rat prostate carcinoma model was used to determine the effects of PTHrP overexpression on prostate tumor growth. PTHrP overexpression did not alter proliferation of the cells in vitro. However, when PTHrP-overexpressing cells were injected into rat hind limbs, primary tumor growth and tumor size were significantly enhanced as compared with control cells. To evaluate PTHrP in human prostate carcinoma patients, immunohistochemistry was performed on metastatic bone lesions. Immunolocalization of PTHrP protein was found in the cytoplasm and nucleus of cancer cells in the bone microenvironment. Because nuclear localization of PTHrP has been associated with an inhibition of apoptosis, the ability of full-length PTHrP to protect prostate cancer cells from apoptotic stimuli was examined. Cells transfected with full-length PTHrP showed significantly increased cell survival after exposure to apoptotic agents as compared with cells producing no PTHrP (plasmid control) or cells transfected with PTHrP lacking its nuclear localization signal. To determine the mechanism of action of PTHrP in prostate cancer cells, the parathyroid hormone/PTHrP receptor status of the cells was determined. These cell lines did not demonstrate parathyroid hormone/PTHrP receptor-mediated binding of iodinated PTHrP or steady-state receptor message by Northern blot analysis, but they did have a detectable receptor message by reverse transcription-PCR analysis. In summary, PTHrP is expressed in many prostate cancer cell lines in vitro and in metastatic bone lesions in vivo. PTHrP expression positively influences primary tumor size in vivo and protects cells from apoptotic stimuli. These data suggest that PTHrP plays an important role in the promotion of prostate tumor establishment and/or progression.
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PMID:Parathyroid hormone-related protein as a growth regulator of prostate carcinoma. 1060 51

We describe a patient with androgen-independent prostate cancer in whom hypocalcemia developed during treatment with estramustine. The patient's total serum calcium level before and after the initiation of estramustine was 8.3 and 4.3 mg/dL, respectively (normal range 8.4 to 10.2). This finding prompted us to review the calcium levels in 135 consecutive patients who were also undergoing treatment with a similar estramustine-containing regimen. We found that hypocalcemia had developed in 20% of these patients during treatment. We speculate that estramustine may cause hypocalcemia by inhibiting the mobilization of calcium and the action of the parathyroid hormone in the skeleton.
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PMID:Estramustine-related hypocalcemia in patients with prostate carcinoma and osteoblastic metastases. 1144 94

Parathyroid hormone-related peptide is a regulatory protein implicated in the pathogenesis of bone metastases, particularly in breast carcinoma. Parathyroid hormone-related peptide is widely expressed in primary prostate cancers but there are few reports of its expression in prostatic metastases. The aim of this study was to examine the expression of parathyroid hormone-related peptide and its receptor in matched primary and in bone metastatic tissue from patients with untreated adenocarcinoma of the prostate. Eight-millimetre trephine iliac crest bone biopsies containing metastatic prostate cancer were obtained from 14 patients from whom matched primary tumour tissue was also available. Histological grading was performed by an independent pathologist. The cellular location of mRNA for parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was identified using in situ hybridization with (35)S-labelled probe. Expression of parathyroid hormone-related peptide and its receptor was described as uniform, heterogenous or negative within the tumour cell population. Parathyroid hormone-related peptide expression was positive in 13 out of 14 primary tumours and in all 14 metastases. Receptor expression was evident in all 14 primaries and 12 out of 14 metastases. Co-expression of parathyroid hormone-related peptide and parathyroid hormone-related peptide receptor was common (13 primary tumours, 12 metastases). The co-expression of parathyroid hormone-related peptide and its receptor suggest that autocrine parathyroid hormone-related peptide mediated stimulation may be a mechanism of escape from normal growth regulatory pathways. The high frequency of parathyroid hormone-related peptide expression in metastases is consistent with a role in the pathogenesis of bone metastases.
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PMID:Parathyroid hormone related peptide and receptor expression in paired primary prostate cancer and bone metastases. 1187 91

This Phase I study of 1alpha-hydroxyvitamin D(2), an p.o. administered vitamin D analogue, in patients with advanced hormone-refractory prostate cancer was designed to assess the toxicity, pharmacokinetic and biological markers of drug activity, and lastly tumor response data to recommend a dose for Phase II studies. 1alpha-Hydroxyvitamin D(2) was administered daily at doses ranging from 5 to 15 microg/day. Patients were monitored for toxicity and tumor response, and blood and urine samples were collected for pharmacokinetics (1alpha,25-dihydroxyvitamin D(2) levels) and other parameters of biological activity (bone markers, parathyroid hormone, urine calcium, and serum phosphorus levels). Twenty-five patients were enrolled. Main toxicities were hypercalcemia with associated renal insufficiency. No other significant toxicity was seen. Pharmacokinetics showed an increase in the active metabolite 1alpha,25-dihydroxyvitamin D(2) that reached a plateau by week 4 despite continuous drug dosing. Elevation in daily urinary calcium excretion and serum phosphorus levels was seen, whereas a decrease in serum parathyroid hormone was evident. Two patients showed evidence of a partial response, whereas 5 others achieved disease stabilization for > or =6 months. 1alpha-Hydroxyvitamin D(2) was well tolerated with main toxicities being hypercalcemia and renal insufficiency. All of the toxicity was reversible with drug discontinuation. Evidence for drug activity was seen in surrogate markers, and pharmacokinetic analysis showed substantial increases in vitamin D metabolite levels among the various cohorts. Whereas the defined maximum tolerated dose was not reached, the recommended Phase II dose was 12.5 microg/day given continuously.
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PMID:Phase I trial of 1alpha-hydroxyvitamin d(2) in patients with hormone refractory prostate cancer. 1223 22

Parathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP increases the growth and enhances the osteolytic effects of prostate cancer cells, it is important to control the level of PTHrP expression in these cells. We show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its non-calcemic analogue, EB1089, suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines PC-3 and LNCaP. The human PTHrP gene contains a sequence element homologous to the negative vitamin D response element within the parathyroid hormone gene. This DNA sequence (nVDRE(hPTHrP)) bound the vitamin D receptor (VDR) present in nuclear extracts from both PC-3 and LNCaP cells. However, when cloned upstream of the SV40 promoter and transiently transfected into PC-3 and LNCaP cells, nVDRE(hPTHrP) downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP, but not in PC-3, cells. These results may help to explain why some prostate cancers appear to be refractory to treatment with vitamin D analogues.
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PMID:Prostate cancer cell type-specific regulation of the human PTHrP gene via a negative VDRE. 1285 Feb 81

The hormonal form of vitamin D, 1 alpha,25-dihydroxyvitamin D [1 alpha,25(OH)(2)D] promotes the differentiation and inhibits the proliferation, invasiveness and metastasis of prostate cells. However, 1 alpha,25(OH)(2)D is not suitable as a chemopreventive agent because its administration can cause hypercalcemia. Serum levels of 1 alpha,25(OH)(2)D are tightly regulated by the renal enzyme, 25-hydroxyvitamin D-1 alpha-hydroxylase (1 alpha-OHase), which synthesizes 1 alpha,25(OH)(2)D from the prohormone, 25-hydroxyvitamin D [25(OH)D]. Normal prostate epithelial cells in primary culture, as well as several prostate cancer cell lines, also express 1 alpha-OHase and synthesize the hormone intracellularly. We now investigated the regulation of the prostate 1 alpha-OHase by the three most important regulators of the renal 1 alpha-OHase: calcium, 1 alpha,25(OH)(2)D and parathyroid hormone (PTH). The 1 alpha-OHase activity in the primary cultures of prostate epithelial cells was inhibited by 1 alpha,25(OH)(2)D(3) at 10 and 100 nM, whereas PTH at 10 and 100 nM had no significant effect. Calcium at 1.2 and 2.4 mM had no significant effect on the enzyme activity in the PZ-HPV-7 cell line, a prostate epithelial cell line derived from normal prostate tissue. Conversely, 1.2 or 2.4 mM calcium markedly inhibited 1 alpha-OHase activity in a human kidney cell line used as a positive control. Furthermore, PTH at 100 nM and calcium at 1.2 and 2.4 mM had no effect on the 1 alpha-OHase gene promoter activity in prostate cells, whereas the promoter activity was inhibited 48 +/- 5% by 100 nM 1 alpha,25(OH)(2)D(3). Our findings suggest that, unlike the renal enzyme, the prostate 1 alpha-OHase appears to be largely unregulated by serum levels of PTH and calcium. These findings support the hypothesis that vitamin D or 25(OH)D may be useful as chemopreventive agents for prostate cancer because their administration should cause an increased synthesis of 1 alpha,25(OH)(2)D within prostate cells.
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PMID:The prostate 25-hydroxyvitamin D-1 alpha-hydroxylase is not influenced by parathyroid hormone and calcium: implications for prostate cancer chemoprevention by vitamin D. 1472 78


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