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

Cancer patients, particulary those with bone metastatses, are at high risk of skeletal complications. Patients with advanced cancer and bone metastatses freguently experience debilitating skeletal complications that can substantially affect their quality of life.Many types of cancer metastasize to the bone, but breast and prostate cancer account for roughly 70-80% of bone metastatses. Bisphosphonates have emerged as a leading therapeutic intervention for the treatment and prevention of sceletal complications of malignancy. Bisphosphonates have a variety of activities in bone and can effectively normalize serum calcium, delay the onset and reduce the incidence of sceletal complications, and may reduce bone pain. Zoledronic Acid is highly potent, new-generation, nitrogen-containing bisphosphonate that has superior potency and pharmacologic properties compared with other bisphosphonates. It has been shown to be highly effective in the treatment of osteolitic, mixed and osteoblastic bone metastatses in patients with breast cancer and prostate cancer.
 ...
PMID:Zoledronic Acid in the treatment of bone metastases from the breast and prostate carcinoma. 1803 35

There is considerable evidence for an association between prostate cancer development and inflammation, which results in autoantibody generation against tumor proteins. This immune system-driven amplification of the autoantibody response to intracellular antigens can serve as a sensitive tool to detect low abundance serum proteomic tumor markers for prostate cancer as well as provide insight into biological processes perturbed during cancer development. Here we examine serum humoral responses in a cohort of 34 patients with either benign prostatic hyperplasia or clinically localized prostate cancer (PCa). The experimental strategy couples multidimensional liquid-phase protein fractionation of localized and metastatic prostate cancer tissue lysates to protein microarrays and subsequent mass spectrometry. A supervised learning analysis of the humoral response arrays generated a parsimonious predictor having 78% sensitivity and 75% specificity in distinguishing PCa from benign prostatic hyperplasia in a cohort of American males with elevated prostate-specific antigen. Enrichment analysis of the PCa-specific humoral signature revealed large scale immune reprogramming mediated by STAT transcription factors and the generation of autoantibodies to enzymes involved in nitrogen metabolism. Meta-analysis of independent prostate cancer gene expression data validated the presence of STAT-induced immunomodulation. Concomitant validation of elevated levels of the nitrogen metabolism pathway was obtained by direct measurement of metabolic levels of glutamate and aspartate in prostate cancer tissues. Thus, in addition to functioning as markers in prostate cancer detection, humoral response profiles can serve as powerful tools revealing pathway dysregulation that might otherwise be suppressed by the complexity of the cancer proteome.
 ...
PMID:Humoral response profiling reveals pathways to prostate cancer progression. 1807 43

Many constitutional analogues of estrogen have been reported. In this review, the application, action(s), and mechanism(s) of clinically used synthetic estrogens are described. Estramustine and phosphestrol have been used for many years in the treatment of advanced prostate cancer. Estramustine phosphate is a prodrug that is rapidly on oral administration to the five metabolites, estramustine, estromustine, estradiol, estrone and anticancer drug, nitrogen mustards. Estramustine induces dose- and time-dependent metaphase arrest and breakdown of interphase microtubules. Raloxifene is a selective estrogen receptor modulator from the benzothiophene class that binds to the estrogen receptor and has estrogen-agonist effects on bone. Raloxifene has used in female patients with postmenopausal osteoporosis.
 ...
PMID:[Synthetic estrogens: some new pharmacological actions and mechanisms]. 1818 55

Zoledronic acid (Zometa is a third-generation nitrogen-containing parenteral bisphosphonate indicated for the treatment of bone metastases due to solid tumours or multiple myeloma and for hypercalcaemia of malignancy (HCM). In patients with advanced breast or prostate cancer, zoledronic acid 4 mg every 3-4 weeks for up to 15 months significantly reduced the proportion of patients with > or =1 skeletal-related event (SRE), excluding HCM, compared with placebo. In patients with advanced breast cancer or multiple myeloma, the incidence of SREs was similar in patients treated with zoledronic acid 4 mg or pamidronic acid 90 mg every 3-4 weeks for up to 25 months but, in breast cancer patients, zoledronic acid reduced the risk of SREs, including HCM, by an additional 20% compared with pamidronic acid. In modelled cost-utility studies comparing direct costs based on efficacy and resource-use data from these and/or other trials, results have varied. In the most recent study performed from the perspective of the UK NHS and modelled over a 10-year treatment period in women with advanced breast cancer, intravenous zoledronic acid and oral ibandronic acid were dominant over no treatment. Intravenous zoledronic acid was the most cost effective, in terms of incremental costs per QALY gained, followed by oral ibandronic acid, intravenous pamidronic acid and intravenous ibandronic acid. Two other modelled analyses in patients with advanced breast cancer, also conducted from the perspective of the NHS, evaluated the cost utility of three bisphosphonate therapies in patients receiving hormonal therapy or intravenous chemotherapy. Analyses were modelled over 14.3 months (i.e. expected survival) and assumptions varied markedly from results in clinical breast cancer trials. Also, efficacy assumptions for zoledronic acid were not based on clinical trials with the drug. The results of these analyses suggest that oral ibandronic acid is more cost effective than intravenous zoledronic acid and intravenous pamidronic acid in terms of incremental cost per QALY gained. In a global, 15-month modelled cost-effectiveness analysis of patients with advanced prostate cancer, conducted from a third-party perspective, the incremental cost per QALY gained for zoledronic acid versus no treatment was $US159 200 (year 2000 value), which is about 3-fold greater than commonly accepted thresholds for cost effectiveness. In conclusion, a recent modelled economic analysis suggests that intravenous zoledronic acid 4 mg is dominant relative to no treatment in the management of bone metastases in patients with advanced breast cancer. In contrast, in patients with advanced prostate cancer, the incremental cost per QALY gained for zoledronic acid 4 mg versus no treatment was predicted to be higher than commonly accepted thresholds. Compared with other bisphosphonates in the setting of advanced breast cancer, intravenous zoledronic acid was more cost effective than oral or intravenous ibandronic acid and intravenous pamidronic acid in one study, but less cost effective than oral ibandronic acid in another. Further efficacy and economic data comparing intravenous zoledronic acid with oral ibandronic acid are needed. Meanwhile, zoledronic acid appears to be the most cost effective intravenous bisphosphonate for the management of bone metastases in patients with advanced breast cancer and possibly in patients with different types of advanced solid tumours.
 ...
PMID:Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases. 1828 18

Bisphosphonates (BPs) are effective inhibitors of tumor-induced bone resorption. Recent studies have demonstrated that BPs inhibit growth, attachment and invasion of cancer cells in culture and promote apoptosis. The mechanisms responsible for the observed anti-tumor effects of BPs are beginning to be elucidated. Recently, we reported that nitrogen-containing bisphosphonates (N-BPs) induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of farnesyl diphosphate synthase in the mevalonate pathway. Similar to AppCp-type metabolites of non-N-BPs, ApppI is able to induce apoptosis. This study investigated BP-induced ATP analog formation and its effect on cancer cell growth. To evaluate zoledronic acid (a N-BP)-induced ApppI accumulation, inhibition of protein prenylation and clodronate (a non-N-BP) metabolism to AppCCl2p, MCF-7 and MDA-MB-436 breast cancer cells, MCF-10A nonmalignant breast cells, PC-3 prostate cancer cells, MG-63 osteosarcoma cells, RPMI-8226, and NCI-H929 myeloma cells were treated with 25 micromol/l zoledronic acid or 500 micromol/l clodronate for 24 h. The inhibition of cell growth by zoledronic acid and clodronate was studied in MCF-7, MDA-MB-436, and RPMI-8226 cells by exposing the cells with 1-100 micromol/l zoledronic acid or 10-2000 micromol/l clodronate for 72 h. Marked differences in zoledronic acid-induced ApppI formation and clodronate metabolism between the cancer cell lines were observed. The production of cytotoxic ATP analogs in tumor cells after BP treatment is likely to depend on the activity of enzymes, such as farnesyl diphosphate synthase or aminoacyl-tRNA synthetases, responsible for ATP analog formation. Additionally, the potency of clodronate to inhibit cancer cell growth corresponds to ATP analog formation.
 ...
PMID:Bisphosphonate-induced ATP analog formation and its effect on inhibition of cancer cell growth. 1845 49

Using a live cell, high-throughput caspase-3 activator assay, we have identified a novel series of 4-anilinoquinazolines as inducers of apoptosis. In this report, we discuss the discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine, compound 2b (EP128265, MPI-0441138) as a highly active inducer of apoptosis (EC50 for caspase activation of 2 nM) and as a potent inhibitor of cell proliferation (GI50 of 2 nM) in T47D cells. Compound 2b inhibited tubulin polymerization, was effective in cells overexpressing ABC transporter Pgp-1, and was efficacious in the MX-1 human breast and PC-3 prostate cancer mouse models. In contrast to the SAR of 4-anilinoquinazolines as EGFR kinase inhibitors, the methyl group on the nitrogen linker was essential for the apoptosis-inducing activity of 4-anilinoquinazolines and substitution in the 6- and 7-positions of the quinazoline core structure decreased potency.
 ...
PMID:Discovery of 2-chloro-N-(4-methoxyphenyl)-N-methylquinazolin-4-amine (EP128265, MPI-0441138) as a potent inducer of apoptosis with high in vivo activity. 1865 28

Prometastatic gene expression events occur during the early phases of prostate oncogenesis, even though overlaping with genes that induce primary cancer growth. Cytogenetic and genomic profiling analyses have identified many cancer-associated chromosomal abnormalities consisting mainly in losses in the early phases of sporadic primary prostate carcinoma. Metastatic genes are those in which gains in oncogene functional activity or lack of tumor suppressor genes enable cancer cells to detach, escape into the circulation, penetrate and colonize distant organs. In metastatic prostate carcinoma some genes, such as MTA1 and MYBL2, are differentially upregulated in comparison to primary site, while IGFBP, DAN1, FAT and RAB5A appear to be downregulated. Epigenetic alterations, such as histone deacetylation/hypermethylation, are also involved in the metastasis promotion. Nevertheless, during oncogenesis and cancer progression, prostate cancer cells may regain pluripotent stem cell-like properties or, as an alternative, may be, them selves, malignant stem cell clones, equipped with self-renewal mechanisms. Pleiotropic contributions to cancer progression and metastatic spread are also brought up from a variety of tumor microenvironment-associated factors. Moreover, inflammatory processes can partecipate in prostate tumorigenesis and cancer progression through several mechanisms, such as generation of both oxygen and nitrogen reactive species, induction of cyclooxygenase-2 and production of growth factors and cytokines by neutrophils and macrophages of host microenvironment. The knowledge of both genetic and microenvironmental cancer aggressiveness factors is necessary to define timing and suitability of therapeutical strategies.
 ...
PMID:Genetic and microenvironmental implications in prostate cancer progression and metastasis. 1870 Jun 88

Bisphosphonates (BPs), as inhibitors of osteoclasts, are widely used in the management of metastatic bone disease and in the prevention of osteomalacia and osteoporosis. Recent cases of bone necrosis of the jaws have been associated with the use of bisphosphonate therapy. A case is presented of a patient with osteonecrosis of the maxilla with a history of long-term bisphosphonate therapy for metastatic breast cancer. The authors treated the patient and suggest appropriate patient management guidelines with reference to current knowledge. Although a definitive treatment for bisphosphonate-associated osteonecrosis has not yet been established, clinicians must be aware of the pharmacologic properties of several bisphosphonates currently available and their indications, susceptible risk factors in the development of osteonecrosis of the jaws, the clinical signs and symptoms, and recommendations for patient management, including prevention and early recognition. BPs, potent inhibitors of osteoclast-mediated bone resorption, were first introduced more than 20 years ago. Since then, they have been used widely in the management of bone diseases, including hypercalcemia related to malignancy, myeloma-related bone disease, Paget's disease and osteoporosis. They have also been shown to inhibit tumor cell proliferation and inhibit angiogenesis. These additional features have made BPs useful in the treatment of metastatic disease, including breast and prostate cancer, resulting in a rise in the medical use of these drugs. However, recent reports suggest that BPs, particularly the nitrogen-containing BPs pamidronate (Aredia) and zoledronic acid (Zometa), both manufactured by Novartis of East Hanover, NJ, are capable of causing bisphosphonate-associated osteonecrosis of the jaw (BON). With 2.5 million patients treated with pamidronate and/or zoledronate worldwide, BON occurs in about one per 10,000 treated patients (Novartis, unpublished data, 2004). Currently, the total number of reported cases associated with alendronate (Fosamax, Merck and Co. Inc., White-house Station, NJ) the most commonly prescribed oral bisphosphonate, is approximately 170 worldwide (C. Arsver, oral communication, March 2006). This corresponds to a spontaneous BON incidence of approximately 0.7 cases per 100,000-years exposure. However, there is insufficient data to determine why the osteonecrosis reported seems to particularly affect the jaw, with a slightly higher rate in the mandible than the maxilla. This report concerns the management of a patient with BON. Information provided includes: the pharmacologic properties of the several bisphosphonates currently available; the pathobiological mechanism; the clinical presentation of the oral lesions; and recommendations for the oral management of patients who have received BP therapy, with consideration of a preventative approach based on current knowledge.
 ...
PMID:Bisphosphonate-associated osteonecrosis: a clinician's reference to patient management. 1876 52

Lately clinical evidence has suggested that the development of osteonecrosis of the jaws (ONJ) might be associated to assumption of high doses of nitrogen-bisphosphonate (N-BPs), quite common in the treatment of multiple myeloma and skeletal metastasis due to breast and prostate cancer. Bisphosphonates are used for the treatment of several pathologies such as osteoporosis, Paget's disease, multiple myeloma, malignant hypercalcemia, breast and prostate tumours, and other tumours associated with bone metastasis. Their use might improve patient's life standard, reducing pain and complications of the skeletal structure. In this report three clinical cases of ONJ of patients in treatment with BPs are presented, and the possible pathogenesis is analysed. Further-more, treatment guidelines for the management of patients in treatment with BPs who need restorative dental care and oral surgery are proposed.
 ...
PMID:Clinical guidelines for prevention of osteonecrosis of the jaws in patients in treatment with bisphosphonates: literature review and report of three cases. 1892 78

Chronic inflammation is a risk factor for many diseases of aging. Endogenous oxidants are thought to mediate the effects of inflammation and gamma-Tocopherol (gamma-Toc) may mitigate damage from nitrogen-based oxidants; however, no physiological requirement for gamma-Toc has been established. Regulation of tocopherols and their functional significance are poorly defined, thereby limiting their application in prevention. Using stored plasma samples from 657 male control subjects in a previous study of prostate cancer, we have analyzed associations of the tocopherols, inflammation markers, and 25-hydroxy (OH) vitamin D. Plasma alpha-Toc and gamma-Toc were inversely correlated, whereas delta-Toc and alpha-Toc levels were positively correlated, suggesting a unique regulatory mechanism. gamma-Toc levels were positively and alpha-Toc negatively associated with plasma C-reactive protein (CRP) and urinary isoprostane F(2t), which are markers of inflammation and oxidation. Ethnic variability in tocopherols was observed; however, this may be explained by differences in plasma 25-OH vitamin D, as gamma-Toc levels varied inversely and alpha-Toc positively with 25-OH vitamin D. In these data, all-cause mortality appeared to be positively associated with CRP and inversely with 25-OH vitamin D. We hypothesize that plasma levels of tocopherols may serve as markers of systemic inflammation, complicating epidemiologic assessment of their role in cancer etiology.
 ...
PMID:Elevated plasma gamma-tocopherol and decreased alpha-tocopherol in men are associated with inflammatory markers and decreased plasma 25-OH vitamin D. 1900 77


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>