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 metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered PTH to induce bone turnover and increase marrow cellularity daily 1 wk before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 wk. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and tartrate-resistant acid phosphatase 5b and in the number of tartrate-resistant acid phosphatase-positive osteoclasts per millimeter of bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by 5-bromo-2'-deoxyuridine immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.
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PMID:Bone turnover mediates preferential localization of prostate cancer in the skeleton. 1563 91

Atrasentan (A-147627) is an endothelin antagonist receptor being developed at Abbott Laboratories for the treatment of prostate cancer. A quick and sensitive method for the determination of atrasentan in human plasma has been developed and validated using high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. A dual-column, single mass spectrometer system is used to provide a reliable and routine means to increase sample throughput. The analytical method involves liquid-liquid extraction and internal standard (A-166790). The plasma samples and internal standard are acidified with 0.3 M hydrochloric acid prior to being extracted into 1:1 (v/v) hexanes--methyl t-butyl ether. The organic extract was evaporated to dryness using heated nitrogen stream and reconstituted with mobile phase. Atrasentan and internal standard were separated with no interference in a Zorbax SB-C(18) analytical column with 2.1 x 50 mm, 5 microm, and a Zorbax C(8) guard column using a mobile phase consisting of 50:50 (v:v) acetonitrile--0.05 M ammonium acetate, pH 4.5, at a flow rate of 0.30 mL/min to provide 4 min chromatograms. For a 250 microL plasma sample volume, the limit of quantitation was approximately 0.3 ng/mL. The calibration was linear from 0.30 to 98.0 ng/mL (r(2) > 0.995). A significant advantage of the method is the ability to employ parallel HPLC separations with detection by a single MS/MS system to provide sensitivity and selectivity sufficient to achieve robust analytical results with a lower limit of quantitation of 0.30 ng/mL and high throughput.
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PMID:High-throughput determination of atrasentan in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. 1580 46

Bone metastasis is an important cause of morbidity in advanced prostate cancer. Bisphosphonates are widely used for the treatment and prevention of osteoporosis, but recently have been observed to be effective in controlling prostate cancer metastasis. Since aminopeptidase N (AP-N) is known to be involved in the metastasis of prostate cancer, we investigated the effect of bisphosphonate on AP-N expression. Incadronate induced inhibition of AP-N mRNA and protein expression in PC-3 cells. The inhibitory effect of AP-N mRNA expression was also observed in the cells treated with pravastatin and other nitrogen-containing bisphosphonates, which inhibit the key enzyme in the isoprenoid biosynthesis pathway. The decrease of AP-N mRNA expression induced by incadronate was inhibited by co-incubation with geranylgeranyl diphosphate (GGPP). Moreover, GGTI-286 treatment also resulted in reduced AP-N mRNA expression. The translocation of small G protein Rap1 from the cytosol to the membrane was inhibited by incadronate and pravastatin, respectively. These above results indicate that the decrease in AP-N expression elicited by bisphosphonate is related to the inhibition of the mevalonate pathway.
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PMID:Incadronate inhibits aminopeptidase N expression in prostatic PC-3 cells. 1601 30

Bone metastases are a major cause of cancer morbidity. Bone metastases are associated with pain, fractures, spinal cord compression, ineffective haematopoiesis, and hypocalcaemia of malignancy. The goals of treatment for bone metastases are to prevent disease-related skeletal complications, palliate pain, and maintain quality of life. Bisphosphonates are a standard part of supportive care for patients with bone metastases. Zoledronic acid, a nitrogen containing third generation bisphosphonate, is the most active and is the most thoroughly investigated bisphosphonate for metastatic bone disease. The efficacy and safety of zoledronic acid has been established in three pivotal prospective, randomized controlled trials involving more than 3000 subjects. The evidence is reviewed here with a focus on clinical relevance. Across a broad array of tumour types, zoledronic acid (4 mg intravenously over 15 min every 3-4 weeks) decreased the frequency of skeletal-related events, delayed the time to a first skeletal-related event, and reduced pain. Zoledronic acid is more effective than pamidronate in breast cancer and the only bisphosphonate proven effective for metastatic prostate cancer, lung cancer, renal cell carcinoma and other solid tumours.
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PMID:Zoledronic acid to prevent skeletal complications in cancer: corroborating the evidence. 1622 55

Biphosphonates (BPs) are widely used to inhibit osteoclastic activity in malignant diseases such as bone metastatic breast and prostate carcinoma. Recent studies reported that BPs could also cause a direct antitumor effect, probably due to their ability to interfere with several intracellular signalling molecules. The enzyme cyclooxygenase-2 (COX-2) and the epidermal growth factor receptor (EGFR) play an important role in the control of cancer cell growth and inhibitors of COX-2 and EGFR have shown antitumor activity in vitro and in vivo in several tumor types. We, and others, have previously shown that EGFR and COX-2 may be directly related to each other and that their selective inhibitors may have a cooperative effect. In the present study we have evaluated the combined effect of zoledronic acid, the most potent nitrogen-containing BP, with the COX-2 inhibitor SC-236 and the selective EGFR-tyrosine kinase inhibitor gefitinib, on breast and prostate cancer models in vitro and in xenografted nude mice. We show that combination of zoledronic acid with SC-236 and gefitinib causes a cooperative antitumor effect accompanied by induction of apoptosis and regulation of the expression of mitogenic factors, proangiogenic factors and cell cycle controllers both in vitro and in xenografted nude mice. The modulatory effect on protein expression and the inhibitory effect on tumor growth is much more potent when the three agents are used together. Since studies are ongoing to explore the antitumor effect of zoledronic acid, our results provide new insights into the mechanism of action of these agents and a novel rationale to translate this feasible combination treatment strategy into a clinical setting.
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PMID:Zoledronic acid cooperates with a cyclooxygenase-2 inhibitor and gefitinib in inhibiting breast and prostate cancer. 1632 42

Positron emission tomography (PET) is perfectly suited for quantitative imaging of the kidneys, and the recent improvements in detector technology, computer hardware, and image processing software add to its appeal. Multiple positron emitting radioisotopes can be used for renal imaging. Some, including carbon-11, nitrogen-13, and oxygen-15, can be used at institutions with an on-site cyclotron. Other radioisotopes that may be even more useful in a clinical setting are those that either can be obtained from radionuclide generators (rubidium-82, copper-62) or have a sufficiently long half-life for transportation (fluorine-18). The clinical use of functional renal PET studies (blood flow, glomerular filtration rate) has been slow, in part because of the success of concurrent technologies, including single-photon emission computed tomography (SPECT) and planar gamma camera imaging. Renal blood flow studies can be performed with O-15-labeled water, N-13-labeled ammonia, rubidium-82, and copper-labeled PTSM. With these tracers, renal blood flow can be quantified using a modified microsphere kinetic model. Glomerular filtration can be imaged and quantified with gallium-68 EDTA or cobalt-55 EDTA. Measurements of renal blood flow with PET have potential applications in renovascular disease, in transplant rejection or acute tubular necrosis, in drug-induced nephropathies, ureteral obstruction, before and after revascularization, and before and after the placement of ureteral stents. The most important clinical application for imaging glomerular function with PET would be renovascular hypertension. Molecular imaging of the kidneys with PET is rather limited. At present, research is focused on the investigation of metabolism (acetate), membrane transporters (organic cation and anion transporters, pepT1 and pepT2, GLUT, SGLT), enzymes (ACE), and receptors (AT1R). Because many nephrological and urological disorders are initiated at the molecular and organelle levels and may remain localized at their origin for an extended period of time, new disease-specific molecular probes for PET studies of the kidneys need to be developed. Future applications of molecular renal imaging are likely to involve studies of tissue hypoxia and apoptosis in renovascular renal disease, renal cancer, and obstructive nephropathy, monitoring the molecular signatures of atherosclerotic plaques, measuring endothelial dysfunction and response to balloon revascularization and restenosis, molecular assessment of the nephrotoxic effects of cyclosporine, anticancer drugs, and radiation therapy. New radioligands will enhance the staging and follow-up of renal and prostate cancer. Methods will be developed for investigation of the kinetics of drug-delivery systems and delivery and deposition of prodrugs, reporter gene technology, delivery of gene therapy (nuclear and mitochondrial), assessment of the delivery of cellular, viral, and nonviral vectors (liposomes, polycations, fusion proteins, electroporation, hematopoietic stems cells). Of particular importance will be investigations of stem cell kinetics, including local presence, bloodborne migration, activation, seeding, and its role in renal remodeling (psychological, pathological, and therapy induced). Methods also could be established for investigating the role of receptors and oncoproteins in cellular proliferation, apoptosis, tubular atrophy, and interstitial fibrosis; monitoring ras gene targeting in kidney diseases, assessing cell therapy devices (bioartificial filters, renal tubule assist devices, and bioarticial kidneys), and targeting of signal transduction moleculas with growth factors and cytokines. These potential new approaches are, at best, in an experimental stage, and more research will be needed for their implementation.
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PMID:Future direction of renal positron emission tomography. 1635 95

Flutamide, a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. Current in vitro studies were undertaken to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. NADPH- and GSH-supplemented human liver microsomal incubations of flutamide gave rise to a novel GSH conjugate where GSH moiety was conjugated to the flutamide molecule via the amide nitrogen, resulting in a sulfenamide. The structure of the conjugate was characterized by liquid chromatography-tandem mass spectrometry and NMR experiments. The conjugate formation was primarily catalyzed by heterologously expressed CYP2C19, CYP1A2, and, to a lesser extent, CYP3A4 and CYP3A5. The mechanism for the formation of this conjugate is unknown; however, a tentative bioactivation mechanism involving a P450-catalyzed abstraction of hydrogen atom from the amide nitrogen of flutamide and the subsequent trapping of the nitrogen-centered radical by GSH or oxidized glutathione (GSSG) was proposed. Interestingly, the same adduct was formed when flutamide was incubated with human liver microsomes in the presence of GSSG and NADPH. This finding suggests that P450-mediated oxidation of flutamide via a nitrogen-centered free radical could be one of the several bioactivation pathways of flutamide. Even though the relationship of the GSH conjugate to flutamide-induced toxicity is unknown, the results have revealed the formation of a novel, hitherto unknown, GSH adduct of flutamide.
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PMID:Identification of a novel glutathione conjugate of flutamide in incubations with human liver microsomes. 1740 14

We characterized the redox profiles in two different human prostate carcinoma cell lines (LNCaP vs PC3) that are known to exhibit varying degrees of invasiveness/metastatic ability. We confirmed that PC3 cells were more invasive than LNCaP cells through an in vitro analysis. The present study documented higher 8-hydroxy-2'-deoxyguanosine levels in PC3 cells than in LNCaP cells. The levels of lipid peroxidation were higher in LNCaP cells than in PC3 cells. The reduced glutathione (GSH)/glutathione disulfide (GSSG) ratio increased to a greater extent during cell growth in PC3 cells than in LNCaP cells, whereas both reduced GSH and GSSG levels were higher in the medium of PC3 cells than in that of LNCaP cells. The levels of reactive oxygen (ROS) and reactive nitrogen species (RNS), both intracellularly and in the medium, were higher for LNCaP cells than for PC3 cells during cell growth. In addition, our results demonstrated higher ROS/RNS levels in LNCaP cells than in PC3 cells in S and G(2)/M phases of the cell cycle during logarithmic growth. Each cell type showed distinct cytotoxic responses to low-molecular-weight redox-modulating compounds. Our results document that human prostate cancer cell lines of varying degrees of aggressive behavior have distinct redox properties, findings that could lead to novel therapeutic interventions.
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PMID:Characterization of redox state of two human prostate carcinoma cell lines with different degrees of aggressiveness. 1760 30

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural l-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clinical trials. To determine if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 weeks at 0.0125% to 0.1% w/w of the diet. Analysis of safingol and safingol metabolites in blood and tissues by liquid chromatography electrospray ionization tandem mass spectrometry revealed uptake in tissue and extensive conversion of safingol to N-acyl species (comparable to natural "ceramides") and mono-, di-, and tri-N-methyl metabolites that have not been observed previously. Safingol caused significant hepatotoxicity at all dosages, as reflected in elevated liver alanine aminotransferase, and at the highest dose (0.1 %) caused changes in liver histology (appearance of autophagosomal vacuoles) and renal toxicity (based on elevation of blood urea nitrogen) and decreases in packed blood cell volume and body weight. Safingol did not inhibit the prostate pre-neoplastic lesion (prostate intraepithelial neoplasia) in TRAMP mice; however, additional studies at lower dosages for longer time were not pursued due to host toxicity. Safingol and its N-methyl metabolites were cytotoxic to both a human prostate cell line (DU145) and mouse BALB 3T3 cells; therefore, the host and potential antitumor toxicity may be due to multiple molecular species of safingol.
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PMID:Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation. 1761 6

Nitrogen-containing bisphosphonates (nBPs) are bone-specific agents that inhibit farnesyl diphosphate synthase. nBPs' strong affinity for bone, and not for other tissues, makes them potent inhibitors of bone resorption and bone remodeling activity, with limited potential for side-effects in non-skeletal tissues. Five nBPs are currently approved in the United States. The primary indications are for treatment of osteoporosis (alendronate, ibandronate, and risedronate) and treatment/prevention of skeletal-related events (SREs) in multiple myeloma and breast and prostate cancer patients (ibandronate, pamidronate, and zoledronic acid). nBPs are the most efficacious drugs available for these diseases, reducing osteoporotic fracture risk by 50-60% in persons with low bone mass or prior osteoporotic fracture, and SREs by one-third in cancer patients. The absorbed nBP dose for cancer patients is from seven to ten times that in osteoporosis patients. nBPs are unique in that they first exert profound pharmacodynamic effects long after their blood levels reach zero. Current pharmacokinetic studies indicate that approximately half of any nBP dose reaches the skeleton, with an early half-life of ten days, and a terminal half-life of about ten years. Practical study design limitations and theoretical considerations suggest that both the half-life and the amount of nBP retained in the skeletons of patients on long-term nBP therapy are substantially overestimated by extrapolation directly from current pharmacokinetic data. In fact, the amount of nBP being released from skeletal tissues of long-term-treated patients, particularly in osteoporosis patients, becomes insufficient to maintain full pharmacodynamic efficacy relatively soon after dosing is interrupted.
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PMID:Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. 1795 91


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