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)

Bone marrow acid phosphatase has been reported to be a sensitive indicator of early bony metastasis from adenocarcinoma of the prostate. In order to evaluate this hypothesis, we measured bone marrow acid and alkaline phosphatase, lactic dehydrogenase, and calcium levels in a group of 84 patients with a variety of problems, including 18 with cancer of the prostate. We found that the bone marrow acid and alkaline phosphatase and lactic dehydrogenase were elevated and calcium was depressed in most patients. Among patients with prostate cancer, bone marrow acid phosphatase was not significantly different between those with or without bone metastases. In addition, the patients with prostatic cancer did not have higher levels of bone marrow acid phosphatase than subjects with other malignant and nonmalignant conditions. The level of acid and alkaline phosphatase, lactic dehydrogenase and calcium varied predictably with the aspiration technique used and was independent of sex, disease state or method of chemical determination. Due to this variation, we believe that bone marrow enzyme and calcium levels are of no value in the detection of metastases in patients with prostate cancer.
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PMID:Lack of usefulness of bone marrow enzymes and calcium in staging patients with prostatic cancer. 63 3

Androgen-dependent normal prostatic glandular cells and androgen-dependent prostatic cancer cells can be induced to undergo cell death after androgen ablation. This death does not require the cells to proliferate and occurs as an energy-dependent process collectively referred to as "programmed cell death" in which the cells actively commit "suicide." Associated with this programmed cell death pathway is the enhanced expression of a series of genes and the fragmentation of the genomic DNA into nucleosomal oligomers. This genomic DNA fragmentation is the irreversible commitment step in the death of the cell and results from activation of Ca2+/Mg(2+)-dependent endonuclease activity within the cell nucleus. This activation is due to sustained elevation of intracellular free Ca2+ (Cai) induced after androgen ablation. Metastatic prostatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent cancer cells. Thus, androgen ablation is rarely curative since it only induces the programmed death of the androgen-dependent cancer cells without activating this pathway in the androgen-independent cancer cells within the patient. Androgen-independent prostatic cancer cells do not activate this death process after androgen ablation, since this does not induce a sustained increase in Cai. A new approach to treat androgen-independent prostatic cancer cells has focused on the use of chemotherapeutic agents to induce a sustained increase in Cai. These studies demonstrate that if such a sustained elevation in Cai is maintained, even androgen-independent prostatic cancer cells undergo programmed cell death.
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PMID:Androgen regulation of programmed death of normal and malignant prostatic cells. 129 27

To develop a new approach to the treatment of advanced, hormone-refractory prostate cancer, the signal transductions regulating the growth of human androgen-independent prostate carcinoma cell lines were studied. Agonist-stimulated Ca2+ mobilization, a critical regulatory event in other secretory cell types, was studied as a means of identifying previously undescribed plasma membrane receptors that may transduce a growth inhibitory signal. In all of the cell lines tested, P2-purinergic receptor agonists, including ATP and certain hydrolysis-resistant adenine nucleotides, induced a rapid, transient increase in cytoplasmic free Ca2+ that was detectable at 50 to 100 nM ATP, was maximal at 100 microM ATP, and was inhibited approximately 50% by chelation of extracellular Ca2+. Within 8 s after addition, ATP stimulated accumulation of the polyphosphatidylinositol products inositol (1, 4, 5) trisphosphate, inositol (1, 3, 4) trisphosphate, and inositol tetrakisphosphate. In addition to stimulating phosphatidylinositol turnover and Ca2+ mobilization, ATP and hydrolysis-resistant ATP analogues induced greater than 90% inhibition of the growth of all lines tested. These data demonstrate that human androgen-independent prostate carcinoma cells express functional P2-purinergic receptors linked to phospholipase C, and that agonists of this receptor are markedly growth inhibitory, suggesting a novel therapeutic approach to this common adult neoplasm.
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PMID:P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells. 130 35

Prostate-specific antigen (PSA) is the most sensitive marker available for monitoring the progression of prostate cancer and response to therapy. In a previous study, we demonstrated tissue-specific expression of PSA glycoprotein and mRNA and its regulation through the androgen receptor. In this study, we examine the effects of protein kinase A (PKA) and protein kinase C (PKC) on the androgen regulation of PSA in a human adenocarcinoma cell line, LNCaP. Northern blot analysis demonstrated that forskolin, an activator of PKA, had no effect on the androgen regulation of PSA. However, the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a direct activator of PKC, showed a time- and dose-dependent repression of the androgen regulation of PSA glycoprotein and mRNA. The biologically inactive phorbol ester, 4 alpha-phorbol-12,13-didecanoate, had no effect. Staurosporine, a PKC inhibitor, blocked the TPA-mediated repression of the androgenic stimulation of PSA glycoprotein. In addition, the calcium ionophore, A23187, was able to simulate the actions of TPA, presumably through activation of PKC via calcium mobilization. In summary, the androgenic regulation of PSA protein and mRNA is repressed by tumor-promoting phorbol esters through the PKC pathway. This indicates that the effects of TPA may be secondary to repressed gene transcription or altered mRNA stability. In addition, this study emphasizes that the androgenic regulation of PSA is complex and may involve other extracellular transduction signals.
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PMID:Tumor-promoting phorbol ester down-regulates the androgen induction of prostate-specific antigen in a human prostatic adenocarcinoma cell line. 137 17

Although osteosclerotic metastases are characteristic of prostatic carcinoma, bone resorption is also accelerated. Since clodronate inhibits bone resorption and relieves bone pain, we have given it to patients with painful bone disease from prostatic cancer after failure of hormonal therapy. All patients received estramustine phosphate orally. Simultaneously they were randomly allocated to clodronate (36) and placebo (39) groups. Clodronate was given by mouth. The dose was 3.2 g for the first month, thereafter 1.6 g. Pain relief was more distinct in the clodronate group where one third of patients were totally free of bone pain. The use of analgesics stopped in 38% of patients on clodronate and in 18% on placebo which effect probably belongs to estramustine phosphate. Serum calcium concentration decreased more markedly in the clodronate group. Clodronate dose of 3.2 g seemed to be more potent than that of 1.6 g. Side effects were uncommon and occurred equally in both groups. No significant differences were seen in median survival or survival rates between the groups.
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PMID:Effect of oral clodronate on bone pain. A controlled study in patients with metastic prostatic cancer. 138 86

In a controlled trial the effects of the osteoclast inhibitor disodium pamidronate were studied over a 6-month period in men with metastatic bone disease from prostate cancer. Using serial biochemical measurement of metabolic bone activity, and complementary subjective and quantitative bone histology, the effects of pamidronate were evaluated in tumour-free and metastatic regions of the skeleton, enabling analysis of the differential mechanisms of bone destruction in this disease. Following treatment, abnormally high markers of bone breakdown fell significantly (fasting urine hydroxyproline/creatinine (OHP): P less than 0.05; fasting urine calcium excretion (CaE): P less than 0.0001), confirming that activated osteoclasts play an integral role in the osteolytic process. Serial histomorphometry of bone from tumour-free areas showed that pamidronate restored abnormal levels of bone erosion to normal in 93% of cases. Suppression of bone destruction was also evident within metastases, although this was incomplete. The results confirm that osteoclast overactivity is responsible for a significant proportion of the accelerated osteolysis seen in both tumour-free and infiltrated bone in patients with prostate cancer. The differential effects in tumour-free and infiltrated bone suggest that the mechanisms of osteoclast activation may differ in metastatic and non-metastatic regions of the skeleton.
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PMID:Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer. 173 55

To increase survival of men with metastatic prostatic cancer, a modality that can effectively eliminate androgen independent cancer cells is desperately needed. By combining such an effective modality with androgen ablation, all of the heterogeneous populations of tumour cells within a prostatic cancer patient can be affected, thus optimizing the chances of cure. Unfortunately, such effective therapy for the androgen independent prostatic cancer cell is not yet available. This therapy will probably require two types of agents, one having antiproliferative activity affecting the small number of dividing androgen independent cells, and the other able to increase the low rate of cell death among the majority of non-proliferating (ie interphase) androgen independent prostatic cancer cells present. Androgen dependent prostatic epithelial cells can be made to undergo programmed death by means of androgen ablation, even if the cells are not in the proliferative cell cycle. Androgen independent prostatic cancer cells retain the major portion of this programmed cell death pathway, only there is a defect in the pathway such that it is no longer activated by androgen ablation. If the intracellular free Ca2+ is sustained at an elevated level for a sufficient time, androgen independent cells can be induced to undergo programmed death. The long term goal is therefore to develop some type of non-androgen ablative method that can be used in vivo to induce a sustained elevation in Ca2+ in androgen independent prostatic cancer cells. To accomplish this task, a more complete understanding of the biochemical pathways involved in programmed cell death is urgently needed. At present, studies are focusing on the mechanism involved in the Ca2+ elevation in the normal and malignant androgen dependent cell induced following androgen ablation and the role of the TRPM-2 protein in this process.
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PMID:Programmed cell death as a new target for prostatic cancer therapy. 184 55

Androgen ablation induces an energy-dependent process of programmed death in nonproliferating androgen-dependent prostatic cancer cells which involves fragmentation of genomic DNA into nucleosomal oligomers catalyzed by nuclear Ca2+, Mg(2+)-dependent endonuclease enzymes activated following a sustained elevation in intracellular free Ca2+ (Cai). In contrast, androgen-independent prostatic cancer cells are not induced to undergo such programmed cell death by androgen ablation. One explanation for the inability of androgen ablation to induce programmed death of androgen-independent prostatic cancer cells is that such ablation does not result in a sustained elevation in Cai in these cells. This raises the issue of whether androgen-independent prostatic cancer cells can be induced to undergo programmed death if an elevation in the Cai is sufficiently sustained by nonhormonal means. To test this possibility, androgen-independent, highly metastatic Dunning R-3327 AT-3 rat prostatic cancer cells were chronically exposed in vitro to the calcium ionophore ionomycin to sustain an elevation in their Cai. These studies demonstrated that an elevation of Cai as small as only 3-6-fold above baseline can induce the death of these cells if sustained for greater than 12 h. Temporal analysis demonstrated that the death of these cells does not require cell proliferation and involves Ca(2+)-induced fragmentation of genomic DNA into nucleosome-sized pieces as the commitment step in this process. These results demonstrate that even nonproliferating androgen-independent prostatic cancer cells can be induced to undergo programmed cell death if a modest elevation in the Cai is sustained for a sufficient time. These observations identify Cai as a potential target for therapy for androgen-independent prostatic cancer cells.
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PMID:Programmed death of nonproliferating androgen-independent prostatic cancer cells. 187 14

Mibolerone (dimethylnortestosterone) or 5 alpha-dihydrostestosterone (DHT) increase intracellular calcium (Ca2+i) of human prostate cancer cells (LNCaP) as early as 2 min after treatment. These effects were concentration-dependent (10(-6)-10(-12) M) and they were blocked by preincubation with hydroxyflutamide (10(-6) M). Verapamil (10(-6) M) also suppressed the mibolerone (10(-6) M)-induced increase in Ca2+i, in cells which were previously exposed to 1 mM CaCl2 introduced in a Ca(2+)-free media. The results indicate that androgens elicit changes in Ca2+i in LNCaP cells as a result of Ca2+ influx through L-type channels in the plasma membrane. Since androgens are involved in the regulation of prostate cell division and growth, these findings suggest that calcium is involved in metabolic and mitogenic responses to steroid hormone in target cells.
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PMID:Effects of androgen on intracellular calcium of LNCaP cells. 188 94

Twenty five hormone manipulated patients with prostate cancer and metastatic bone disease, treated at least 6/12 previously by hormone manipulation, were given intravenous infusions of Disodium Pamidronate (APD) over a 6 month period. Patients received 30 mg weekly for 4 weeks then twice monthly for 5 months. No other treatment was administered during study. Eleven of 17 patients with pain at the start of the study were pain free at the end. Fasting morning calcium excretion and serum osteocalcin fell significantly with Pamidronate (P less than 0.0001) and urine hydroxyproline was lowered in 13/20 evaluable patients at 6 months. Alkaline phosphatase fell in a proportion of patients and five of 17 patients with previously progressive bone scans stabilised (4) or regressed (1) on treatment. Rising acid phosphatase levels were also lowered in five patients. It is concluded that Pamidronate may be effective in palliating bone pain in some patients and has a stabilising influence on abnormally high bone turnover in metastatic prostate cancer. Further controlled studies of the compound are now warranted.
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PMID:Osteoclast inhibition by pamidronate in metastatic prostate cancer: a preliminary study. 200 84


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