allopurinol and Prostatic-Neoplasms

Topics: Allopurinol; Gout Suppressants; Humans; Male; Prostatic Neoplasms

We determined the toxicity and preliminary response rate of escalating doses of 5-fluorouracil (670 to 1,500 mg./m.2 per day) combined with a fixed dose of interferon-alpha 2b (5 million units) and allopurinol (300 mg. every 8 hours) in cohorts of patients with metastatic prostate cancer.. The trial included 11 men with metastatic prostate cancer. Cohorts of patients received a 5-day constant infusion of 5-fluorouracil combined with subcutaneous interferon-alpha 2b 3 times weekly and allopurinol for 1 week during 5-fluorouracil infusion. Treatment was repeat every 3 weeks.. Of 10 patients evaluable for treatment response and toxicity 3 had a partial response as judged by significant decreases in prostate specific antigen measurements (mean followup 13.5 months). Significant dose limiting toxicities encountered included mucositis, diarrhea and leukoneutropenia.. Further evaluation of this treatment to determine overall response rates and benefit should take into consideration the significant toxicity experienced.

Topics: Aged; Allopurinol; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Prostatic Neoplasms; Recombinant Proteins

Topics: Adult; Aged; Allopurinol; Case-Control Studies; Gout Suppressants; Humans; Hyperuricemia; Male; Middle Aged; Prostatic Neoplasms; Protective Factors; Risk Factors; Taiwan; Uric Acid

Allopurinol reduces oxidative stress and may thus have an anti-inflammatory effect. Previous studies suggest that allopurinol use might decrease the risk of prostate cancer (PCa) among gout patients. We studied the association between allopurinol use and PCa incidence.. The cohort consists of 76,874 men without prevalent PCa, originally identified for the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). The follow-up started at entry to the trial. We excluded men using allopurinol in the year before entry (wash-out). PCa cases detected during 1996-2015 were identified from the Finnish Cancer Registry. Information on tumor Gleason score and TNM stage were obtained from medical files. Information on PSA level was obtained from screening samples for men in the FinRSPC screening arm and from laboratory databases for men in the control arm. Information on BMI was based on a questionnaire sent to men in the FinRSPC screening arm in 2004-2008. Drug purchase information were obtained from the national prescription database. We used Cox regression (adjusted for age, FinRSPC trial arm, PCa family history and use of other medication) to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of PCa risk by allopurinol use. We analyzed medication as a time-dependent variable to minimize immortal time bias.. There were 9062 new PCa diagnoses in the cohort. Follow-up time did not differ by allopurinol use (median 17 yr; IQR 11-19 vs median 17 yr; IQR 12.33-19). The risk of PCa did not differ by allopurinol use (multivariable adjusted HR 1.03; 95% CI 0.92-1.16). Allopurinol use did not associate with the risk of high-grade or metastatic cancer. Cumulative duration or average yearly dose of allopurinol use showed no association with PCa risk. No delayed risk associations were observed in the lag-time analyses.. We observed no difference in the PCa risk by allopurinol use.

Topics: Aged; Allopurinol; Databases, Factual; Drug Prescriptions; Finland; Follow-Up Studies; Gout; Gout Suppressants; Humans; Incidence; Male; Mass Screening; Middle Aged; Neoplasm Grading; Prostate-Specific Antigen; Prostatic Neoplasms; Risk Assessment; Time Factors

Clinical observations indicated an increased risk of developing prostate cancer in gout patients. Chronic inflammation is postulated to be one crucial mechanism for prostate carcinogenesis. Allopurinol, a widely used antigout agent, possesses potent anti-inflammation capacity. We elucidated whether allopurinol decreases the risk of prostate cancer in gout patients.. We analyzed data retrieved from Taiwan National Health Insurance Database between January 2000 and December 2012. Patients diagnosed with gout during the study period with no history of prostate cancer and who had never used allopurinol were selected. Four allopurinol use cohorts (that is, allopurinol use (>365 days), allopurinol use (181-365 days), allopurinol use (91-180 days) and allopurinol use (31-90 days)) and one cohort without using allopurinol (that is, allopurinol use (No)) were included. The study end point was the diagnosis of new-onset prostate cancer. Multivariable Cox proportional hazards regression and propensity score-adjusted Cox regression models were used to estimate the association between the risk of prostate cancer and allopurinol treatment in gout patients after adjusting for potential confounders.. A total of 25 770 gout patients (aged between 40 and 100 years) were included. Multivariable Cox regression analyses revealed that the risk of developing prostate cancer in the allopurinol use (>365 days) cohort was significantly lower than the allopurinol use (No) cohort (adjusted hazard ratio (HR)=0.64, 95% confidence interval (CI)=0.45-0.9, P=0.011). After propensity score adjustment, the trend remained the same (adjusted HR=0.66, 95% CI=0.46-0.93, P=0.019).. Long-term (more than 1 year) allopurinol use may associate with a decreased risk of prostate cancer in gout patients.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Case-Control Studies; Gout; Gout Suppressants; Humans; Male; Middle Aged; Proportional Hazards Models; Prostatic Neoplasms; Risk Factors

Pleiotrophin (PTN) is a heparin-binding growth factor that induces cell migration through binding to its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and integrin alpha v beta 3 (ανβ3). In the present work, we studied the effect of PTN on the generation of reactive oxygen species (ROS) in human endothelial cells and the involvement of ROS in PTN-induced cell migration. Exogenous PTN significantly increased ROS levels in a concentration and time-dependent manner in both human endothelial and prostate cancer cells, while knockdown of endogenous PTN expression in prostate cancer cells significantly down-regulated ROS production. Suppression of RPTPβ/ζ through genetic and pharmacological approaches, or inhibition of c-src kinase activity abolished PTN-induced ROS generation. A synthetic peptide that blocks PTN-ανβ3 interaction abolished PTN-induced ROS generation, suggesting that ανβ3 is also involved. The latter was confirmed in CHO cells that do not express β3 or over-express wild-type β3 or mutant β3Y773F/Y785F. PTN increased ROS generation in cells expressing wild-type β3 but not in cells not expressing or expressing mutant β3. Phosphoinositide 3-kinase (PI3K) or Erk1/2 inhibition suppressed PTN-induced ROS production, suggesting that ROS production lays down-stream of PI3K or Erk1/2 activation by PTN. Finally, ROS scavenging and xanthine oxidase inhibition completely abolished both PTN-induced ROS generation and cell migration, while NADPH oxidase inhibition had no effect. Collectively, these data suggest that xanthine oxidase-mediated ROS production is required for PTN-induced cell migration through the cell membrane functional complex of ανβ3 and RPTPβ/ζ and activation of c-src, PI3K and ERK1/2 kinases.

Topics: Animals; Carrier Proteins; Cell Line, Tumor; Cell Movement; CHO Cells; Cricetulus; CSK Tyrosine-Protein Kinase; Cytokines; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Integrin alphaVbeta3; Male; Phosphatidylinositol 3-Kinases; Prostatic Neoplasms; Reactive Oxygen Species; Receptor-Like Protein Tyrosine Phosphatases, Class 5; Recombinant Proteins; RNA Interference; src-Family Kinases; Xanthine Oxidase

Two new lanostanoids, 3α-acetoxy-22-oxo-5α-lanosta-8,24-dien-21-oic acid, named tsugaric acid D (1) and 16α-hydroxy-3-oxo-5α-lanosta-6,8,24(24(1))-trien-21-oic acid, named tsugaric acid E (2) were isolated from the fruit bodies of Ganoderma tsugae. The structures 1 and 2 were determined by spectroscopic methods. Compound 1 and known compounds 3 and 6 exhibited significant inhibitory effects on xanthine oxidase (XO) activity with an IC50 values of 90.2±24.2, 116.1±3.0, and 181.9±5.8 μM, respectively. Known compound 5 was able to protect human keratinocytes against damage induced by UVB light, which showed 5 could protect keratinocytes from photodamage. The 1 and 5 μM 1 combined with 5 μM cisplatin, respectively, enhanced the cytotoxicity induced by cisplatin. It suggested that 1 and 5 μM 1 combined with low dose of cisplatin may enhance the therapeutic efficacy of cisplatin and reduce side effect and cisplatin resistant.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Biological Products; Cisplatin; Fruiting Bodies, Fungal; Ganoderma; Herb-Drug Interactions; Humans; Inhibitory Concentration 50; Keratinocytes; Lanosterol; Male; Molecular Structure; Phytotherapy; Prostatic Neoplasms; Radiation Injuries, Experimental; Skin Diseases; Xanthine Oxidase

Oestrogen protects cardiovascular health partially via an up-regulation of NO• (NO radical) production. Its synthetic analogue DES (diethylstilbestrol), used as a potent androgen deprivation therapy for patients with prostate cancer, is however associated with high incidence of thromboembolic events. Exposure of BAECs (bovine aortic endothelial cells) to pharmacologically relevant dosage (12.5 μmol/l, 24 h) of DES resulted in a marked reduction in endothelial NO• bioavailability determined by ESR (electron spin resonance), while 17β-oestradiol instead increased NO• production as expected. Intriguingly, endothelial O(2)•- (superoxide anion) production was up-regulated by DES in vitro and in vivo, which was, however, attenuated by the ER (oestrogen receptor) antagonist ICI 182780, the XO (xanthine oxidase) inhibitor oxypurinol or the NOX (NADPH oxidase) inhibitor NSC23766. These agents also restored NO• production. DES alone in a cell-free system did not produce any ESR-sound O(2)•- signal. Of note, eNOS (endothelial NO synthase) mRNA and protein remained unchanged in response to DES. These results suggest that receptor-dependent activation of XO or NOX, and subsequent production of O(2)•-, mediate DES-induced NO• deficiency. This could represent a previously unrecognized mechanism that is responsible for cardiovascular complications of DES administration. Importantly, DES-induced suppression of LNCaP cell invasion and apoptosis were not affected by XO or NOX inhibitor. Therefore combinatorial therapy of DES and XO/NOX inhibitor may prove to be an innovative and useful therapeutic option in eliminating cardiovascular complications of DES, while preserving its anti-cancer effects, benefiting patients with advanced cancer who do not respond well to any other treatments but DES.

Topics: Aminoquinolines; Animals; Apoptosis; Cattle; Cell Movement; Cells, Cultured; Diethylstilbestrol; Electron Spin Resonance Spectroscopy; Endothelium, Vascular; Enzyme Inhibitors; Hydrogen Peroxide; Male; Mice; Mice, Inbred C57BL; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type III; Oxypurinol; Prostatic Neoplasms; Pyrimidines; Reactive Oxygen Species; Superoxides; Tumor Cells, Cultured; Up-Regulation; Xanthine Oxidase

Cancer therapeutic agents that are safe, effective and affordable are urgently needed. We describe that 1'-acetoxychavicol acetate (ACA), a component of Siamese ginger (Languas galanga), can suppress prostate tumor growth by largely abrogating angiogenesis. ACA suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, adhesion and tubulogenesis of primary cultured human umbilical vascular endothelial cells (HUVECs) in a dose-dependent manner. ACA also inhibited VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed new vasculature formation in Matrigel plugs in vivo. We further demonstrated that the mechanisms of this chavicol were to block the activation of VEGF-mediated Src kinase, focal adhesion kinase (FAK) and Rho family of small guanosine triphosphatases (GTPases) (Rac1 and Cdc42 but not RhoA) in HUVECs. Furthermore, treatment of human prostate cancer cells (PC-3) with ACA resulted in decreased cell viability and suppression of angiogenic factor production by interference with dual Src/FAK kinases. After subcutaneous administration to mice bearing human prostate cancer PC-3 xenografts, ACA (6 mg/kg/day) remarkably inhibited tumor volume and tumor weight and decreased levels of Src, CD31, VEGF and Ki-67. As indicated by immunohistochemistry and TUNEL analysis, microvessel density and cell proliferation were also dramatically suppressed in tumors from ACA-treated mice. Taken together, our findings suggest that ACA targets the Src-FAK-Rho GTPase pathway, leading to the suppression of prostate tumor angiogenesis and growth.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Benzyl Alcohols; Blotting, Western; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelium, Vascular; Focal Adhesion Kinase 1; Humans; Male; Mice; Neovascularization, Pathologic; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; rho GTP-Binding Proteins; RNA, Messenger; Signal Transduction; src-Family Kinases; Umbilical Veins; Vascular Endothelial Growth Factor A; Xanthine Oxidase; Xenograft Model Antitumor Assays

Allopurinol has been used for the treatment of gout and conditions associated with hyperuricemia for several decades. We explored the potential of allopurinol on cancer treatment. Allopurinol did not expose cytotoxicity as a single treatment in human hormone refractory prostate cancer cell lines, PC-3 and DU145. However, allopurinol drastically induced apoptosis of PC-3 and DU145 in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a promising candidate for anticancer agent but its efficacy is limited by the existence of resistant cancer cells. We examined the underlying mechanism by which allopurinol overcomes the resistance of prostate cancer cells to TRAIL. Allopurinol up-regulated the expression of a proapoptotic TRAIL receptor, death receptor 5 (DR5). Allopurinol increased DR5 protein, mRNA, and promoter activity. Using DR5 small interfering RNA (siRNA), we showed that allopurinol-mediated DR5 up-regulation contributed to the enhancement of TRAIL effect by allopurinol. Furthermore, we examined the mechanism of allopurinol-mediated DR5 up-regulation. DR5 promoter activity induced by allopurinol was diminished by a mutation of a CAAT/enhancer binding protein homologous protein (CHOP)-binding site. In addition, allopurinol also increased CHOP expression, suggesting that allopurinol induced DR5 expression via CHOP. Allopurinol possesses the activity of a xanthine oxidase (XO) inhibitor. We used XO siRNA instead of allopurinol. XO siRNA also up-regulated DR5 and CHOP expression and sensitized the prostate cancer cells to TRAIL-induced apoptosis. Here, we show the novel potential of allopurinol in cancer treatment and indicate that the combination of allopurinol with TRAIL is effective strategy to expand the TRAIL-mediated cancer therapy.

Topics: Allopurinol; Antimetabolites; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Therapy, Combination; Endoplasmic Reticulum; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Male; Promoter Regions, Genetic; Prostatic Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; Response Elements; RNA, Small Interfering; TNF-Related Apoptosis-Inducing Ligand; Transcription Factor CHOP; Up-Regulation; Xanthine Oxidase

Geum quellyon Sweet, a perennial herb of the Rosaceae family, has been used in the traditional medicine of the Mapuche Amerindians of Chile to treat tooth neuralgia, gastric inflammation, prostatitis and to regulate menstruation, and for its diuretic and aphrodisiac properties. Although many benefits have been claimed for this plant, few scientific studies are available in the literature. In this study, we investigated the antioxidant activity of a methanolic extract of Geum quellyon roots. We also examined the anticancer action of this plant on Caco-2 (colon adenocarcinoma cells), DU-145 (androgen-insensitive prostate cancer cells) and KB (oral squamous carcinoma cells) human tumor cell lines. Our data showed that Geum quellyon extract, containing tannins, exhibits interesting antioxidant properties, expressed by its capacity to scavenge 1,1-diphenyl-2-picryl-hydrazyl radical (DPPH) and superoxide anion (O(2)*-), to inhibit xanthine oxidase activity, to chelate metals, and to protect plasmid DNA from cleavage induced by hydroxyl radicals (*OH) and nitric oxide (NO). These results may explain, at least in part, its use in Mapuche traditional medicine for gastric inflammation and prostatitis. The assays on human tumor cell lines demonstrated that this natural product exhibits a inhibitory effect on all human cancer cells examined, and seem to indicate that necrosis cell death is triggered in KB cells and Caco-2, while apoptotic cell demise appears to be induced in DU-145. The effect evidenced in Caco-2 cells can be in part correlated to a modulation of redox-sensitive mechanisms.

Topics: Antineoplastic Agents, Phytogenic; Antioxidants; Biphenyl Compounds; Caco-2 Cells; Cell Line, Tumor; Chelating Agents; Chile; Comet Assay; DNA, Neoplasm; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Free Radical Scavengers; Geum; Humans; Hydrazines; Hydrogen Peroxide; KB Cells; L-Lactate Dehydrogenase; Male; Medicine, Traditional; Picrates; Plant Extracts; Plant Roots; Prostatic Neoplasms; Reactive Oxygen Species; Tannins; Tetrazolium Salts; Thiazoles; Ultraviolet Rays; Xanthine Oxidase

The ability of the ventral prostate cytosolic fractions to biotransform ethanol to acetaldehyde and 1-hydroxyethyl (1HEt) radicals was tested. Acetaldehyde formation was determined by GC-FID analysis in the head space of incubation mixtures. 1HEt was determined by spin trapping with PBN followed by extraction, silylation of the adduct and GC-MS of the product. Prostate cytosol was able to biotransform ethanol to acetaldehyde in the presence of NADH, hypoxanthine, xanthine, caffeine, theobromine, theophylline, and 1,7-dimethylxanthine but not in the presence of N-methylnicotinamide. All these biotransformations were inhibited by allopurinol and were sensitive to heating for 5 min at 100 degrees C. The biotransformation of ethanol to acetaldehyde in the presence of purines as cosubstrates was accompanied by the formation of hydroxyl and 1HEt radicals as detected by GC-MS, and the process was inhibited by allopurinol. Results suggest that prostate cytosolic xanthine oxidase is able to bioactivate ethanol to acetaldehyde and free radicals. The potential of these processes to be involved in tumor-promoting effects of heavy alcohol drinking in conjunction with high meat and/or purines consumption is analyzed. Multifactorial epidemiological studies considering that possibility might be convenient. Teratogenesis Carcinog. Mutagen. 21:109-119, 2001.

Topics: Acetaldehyde; Alcohol Drinking; Allopurinol; Animals; Antimetabolites; Caffeine; Carcinogens; Chromatography, Gas; Cytosol; Diet; Enzyme Inhibitors; Ethanol; Free Radicals; Gas Chromatography-Mass Spectrometry; Hypoxanthine; Male; Meat; NAD; Neoplasms; Niacinamide; Phosphodiesterase Inhibitors; Prostate; Prostatic Neoplasms; Purines; Rats; Rats, Sprague-Dawley; Spin Trapping; Temperature; Theobromine; Theophylline; Time Factors; Vasodilator Agents; Xanthine; Xanthine Oxidase

Activities of adenosine deaminase (ADA), 5'nucleotidase (5'NT), xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) and levels of thiobarbituric acid reagent substances (TBARS) were measured in 10 cancerous and 10 noncancerous human prostate tissues. Decreased activities of DNA turnover enzymes (ADA and 5'NT), increased activities of GSH-Px and CAT, and unchanged activities of SOD and XO were observed in cancerous prostate tissues compared with those of noncancerous ones. TBARS levels were found to be higher in cancerous tissues than noncancerous ones. In correlation analysis, mostly positive correlations were established between enzyme activities of the cancerous tissues, whereas no meaningful correlations were found between enzyme activities of the noncancerous tissues except for a positive correlation between XO and SOD. The results indicate that the activities of DNA turnover enzymes were reduced, which was possibly an attempt to lower the rate of purine catabolism, and the activities of GSH-Px and CAT enzymes were increased, probably in response to increased free radical stress occurring in cancerous prostate tissues. Increased concentrations of TBARS suggested oxidant stress and thus accelerated peroxidative reactions in the cancerous tissues, even though antioxidant defense mechanisms were activated. These findings suggest that enzymatic antioxidant systems of cancerous prostate tissues cannot sufficiently eliminate oxidant factors and prevent cellular peroxidative reactions occurring during the carcinogenic process.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Aged; Case-Control Studies; Catalase; DNA; Free Radicals; Glutathione Peroxidase; Humans; Male; Middle Aged; Oxidative Stress; Prostatic Neoplasms; Statistics, Nonparametric; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

Cytotoxicity indicated by increased release of prelabeled 51chromium (51Cr) and lactate dehydrogenase (LDH) was studied in human prostate cancer and melanoma cells in cell culture following irradiation or exposure to several injurious substances. These changes were compared to those observed in bovine aortic endothelial cells (BAEC) subjected to identical treatments. Further, the effect of irradiation on plasminogen activator (PA) secretion from prostate cancer cells, and the effect of glycine on radiation-induced cytotoxicity in BAEC were also investigated. Radiation, lipopolysaccharide and xanthine/xanthine oxidase stimulated no release of 51Cr or LDH from tumor cells, while these treatments induced a dose- and time-related loss of those cytotoxic indicators from BAEC. Protease, elastase and Triton X-100 incited loss of 51Cr and LDH from all three cell types. Radiation, lipopolysaccharide and xanthine/xanthine oxidase have been shown to cause cell injury via a common pathogenic pathway of oxidant generation. Tumor cells appear quite resistant to oxidant stress. Cell damage precipitated by protease, elastase and Triton probably involves hydrolysis of proteins and phospholipids in the cell membrane, leading to an increased leakage of intracellular proteins such as LDH and those bound with 51Cr. Radiation caused a dose- and time-related reduction in the secretion of PA from prostate cancer cells. PA is alleged to play a role in tumor metastasis; the reduced secretion could be another beneficial effect of radiation, in addition to interruption of cell proliferation, in the impediment of tumor growth and spread. Glycine diminished cytotoxic injury of BAEC inflicted by radiation. This amino acid may prove useful in offering a degree of protection of normal tissue against radiation associated side-effects.

Topics: Animals; Cattle; Cells, Cultured; Chromium Radioisotopes; Endopeptidases; Endothelium, Vascular; Glycine; Hot Temperature; Humans; L-Lactate Dehydrogenase; Lipopolysaccharides; Male; Melanoma; Pancreatic Elastase; Plasminogen Activators; Polyethylene Glycols; Prostatic Neoplasms; Radiation Injuries; Radiation-Protective Agents; Time Factors; Tumor Cells, Cultured; Xanthine Oxidase; Xanthines

Topics: Administration, Oral; Allopurinol; Drug Antagonism; Drug Therapy, Combination; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Parenteral; Male; Ovarian Neoplasms; Prostatic Neoplasms