allopurinol and Urinary-Bladder-Neoplasms

Our aim is to investigate the risk association between allopurinol use and cancer incidence among gout patients using clinical evidence. Newly diagnosed male patients with gout, 20 years or older, were included after excluding those who had a diagnosis of type 2 diabetes, and were followed up for 12 years in a retrospective cohort study of one million outpatients of a national database. The gout patients were matched to male controls by age and first diagnosis date of gout disease. We then estimated the risk associations between incident cancers and duration of allopurinol use by Cox hazard regression, age-adjusted standardized incidence ratio, and incidence per 1000 person-years. A total of 24 050 gout patients and 76 129 controls were included. The incidence of all-cause cancers for gout patients and controls was 8.26 cases and 7.49 cases/1000 person-years, respectively; it was markedly increased in gout patients who used allopurinol for over 90 days. The hazard ratio of all-cause cancers was 1.21 (95% confidence interval=1.03-1.42, P=0.019) after adjustment for age and 2.26 for bladder cancer (95% confidence interval=1.32-3.87, P=0.003) on comparing those who used allopurinol for over 90 days with nonusers. Meanwhile, other cancers did not show the same significant result. We concluded that those who used allopurinol for a long duration had a higher occurrence of both bladder cancer and all-cause cancers in clinical evidence.

Topics: Adult; Allopurinol; Case-Control Studies; Female; Follow-Up Studies; Gout; Gout Suppressants; Humans; Longitudinal Studies; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Taiwan; Urinary Bladder Neoplasms

A known triterpenoid, β-amyrin (1), and a known and a new phloroglucinol, cohulupone (2) and garcinielliptone P (3), were isolated from the pericarp and heartwood and seed of Garcinia subelliptica, respectively. A new xanthonolignoid, hyperielliptone HF (4), was isolated from the heartwood of Hypericum geminiflorum. The new compounds were established by analysis of their spectroscopic data. Compounds 1-3 showed an inhibitory effect on xanthine oxidase (XO). Treatment of NTUB1, a human bladder cancer cell, with 1 or 1 cotreated with cisplatin for 24 h resulted in a decreased viability of cells. Exposure of NTUB1 to 1 or 1 cotreated with cisplatin for 24 h significantly increased the level of production of reactive oxygen species (ROS). Flow cytometric analysis indicated that treatment of NTUB1 with 1 or 1 cotreated with cisplatin led to the cell cycle arrest, accompanied by an increase in the extent of apoptotic cell death in 1 or 1 combined with cisplatin-treated NTUB1 after 24 h. These data suggested that the presentation of cell cycle arrest and apoptosis in 1 or 1 combined with cisplatin-treated NTUB1 for 24 h was mediated through an increased amount of ROS in cells exposed to 1 or 1 cotreated with cisplatin.

Topics: Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cisplatin; Down-Regulation; Enzyme Inhibitors; Garcinia; Humans; Oleanolic Acid; Phloroglucinol; Plant Extracts; Reactive Oxygen Species; Urinary Bladder Neoplasms; Xanthine Oxidase

It is well known that antioxidants and reactive oxygen species play an important role in carcinogenesis. In this study, we attempted to evaluate antioxidant enzyme activities and lipid peroxidation levels in cancerous bladder tissue and to determine their relationship with bacterial infection. Bacterial culture was made from all urine samples using Blood and Eosin Methylene Blue agars for checking the presence of bacterial infections. We measured thiobarbituric acid reactive substances (TBARs) and activities of xanthine oxidase (XO), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and catalase (CAT) in cancerous tissues of 25 bladder cancer patients, in noncancerous adjacent bladder tissues of 13 out of these 25 patients, and in control bladder tissues of 15 patients with a non-neoplastic genitourinary disease. TBARs levels increased and XO, SOD, GSH-PX, and CAT activities decreased significantly in cancerous bladder tissues. TBARS, XO, and SOD levels were not significantly different between noncancerous adjacent tissue and control bladder tissue. Statistically significantly lower GSH-PX and higher CAT activities were observed in noncancerous adjacent bladder tissue compared with cancerous tissue. GSH-PX level of tumor tissue was correlated significantly with tumor grade (r=-0.425, P=0.034). Results suggested that pathway activity of free radicals were accelerated in the cancerous human bladder tissues via increased TBARs levels and decreased enzyme activities of XO, SOD, GSH-PX, and CAT, which implicated a severe exposure of cancerous tissues to oxidative stress.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Bacterial Infections; Case-Control Studies; Catalase; Female; Glutathione Peroxidase; Humans; Lipid Peroxidation; Male; Middle Aged; Statistics, Nonparametric; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Urinary Bladder Neoplasms; Urinary Tract Infections; Xanthine Oxidase

Phloroglucinols, garcinielliptones HA-HE (1-5), and C (6) were studied in vitro for their inhibitory effects on chemical mediators released from mast cells, neutrophils, and macrophages. Compound 6 revealed significant inhibitory effect on release of lysozyme from rat neutrophils stimulated with formyl-Met-Leu-Phe (fMLP)/cytochalasin B (CB). Compounds 3, 4, and 6 showed significant inhibitory effects on superoxide anion generation in rat neutrophils stimulated with (fMLP)/(CB), while compounds 1 and 5 revealed inhibitory effects on tumor necrosis factor-alpha (TNF-alpha) formation in macrophages stimulated with lipopolysaccharide (LPS). Compounds 1 and 3-6 showed inhibitory effects on xanthine oxidase (XO) and could inhibit the DNA breakage caused by O2(-*). Treatment of NTUB1 with 2 to 60 microM compound 3 and 5 microM cisplatin and SV-HUC1 with 9 to 60 microM 3 and 5 microM cisplatin, respectively, resulted in an increase of viability of cells. These results indicated that compounds 1 and 3-6 showed anti-inflammatory effects and antioxidant activities. Compound 3 mediates through the suppression of XO activity and reduction of reactive oxygen species (ROS), and protection of subsequent cell death.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Cell Death; Cell Line, Tumor; Cisplatin; Enzyme Inhibitors; Garcinia; Humans; Macrophages; Mast Cells; Neutrophils; Phloroglucinol; Rats; Reactive Oxygen Species; Triterpenes; Urinary Bladder Neoplasms; Urothelium; Xanthine Oxidase

Activities of adenosine deaminase (AD), and xanthine oxidase (XO) enzymes were measured in bladder washing fluid (BWF) from 37 patients with bladder cancer. The patients were divided into several groups according to their sex; pattern, number, and depth of the tumors; and tumor grade. There was a statistically significant difference in XO activities between the patients having no tumor and papillary tumor (p < 0.002). The differences in XO values between the patients having no tumor and single tumor; and with no tumor and multiple tumors were statistically significant (p < 0.012, p < 0.016 respectively). XO activities were increased in patients with both papillary and multiple tumors compared to tumor-free group. Regarding to the depth of tumors, only the differences in XO values between the patients having no tumor and superficial tumor was statistically significant (p < 0.037). XO values of patients in grade1 were higher than the patients having no tumor (p < 0.010). AD activities in patients with multiple and invasive tumor were increased compared to patients with single and superficial tumor. AD values in grade 3 were lower than grade 2. However, we did not find any statistically significant differences in AD activities in all groups. As a conclusion, increased XO activity in BWF might be a potentially important finding as an additional diagnostic biochemical tool for bladder cancer. But we could not say this for AD activity. Further investigations in a larger cohort of patients with bladder cancer are needed to enlighten the possible diagnostic role of XO and AD in BWF.

Topics: Adenosine Deaminase; Adult; Aged; Data Interpretation, Statistical; Female; Humans; Male; Middle Aged; Neoplasm Staging; Spectrophotometry, Ultraviolet; Therapeutic Irrigation; Urinary Bladder Neoplasms; Xanthine Oxidase

Activities of adenosine deaminase (ADA), 5'nucleotidase (5NT), xanthine oxidase (XO), superoxide dismutase (SOD), and catalase (CAT) enzymes were measured in cancerous and cancer-free adjacent bladder tissues from 36 patients with bladder cancer and in control bladder tissues from 9 noncancer patients. Increased ADA and decreased XO, SOD, and CAT activities were found in cancerous bladder tissues compared with those of cancer-free adjacent tissues and of control bladder tissues. Differences were also found between enzyme activities in the bladder of different disease stages and grades. In the cancerous tissues, only positive intracorrelations were found, but in the cancer-free adjacent tissues and control tissues, both positive and negative correlations were established between enzyme activities. Results suggested that purine metabolism and salvage pathway activity of purine nucleotides were accelerated in the cancerous human bladder tissues via increased ADA and decreased XO activities, probably together with changes in some other related enzyme activities and, free radical metabolising-enzyme activities were depressed in cancerous bladder tissues, which indicated exposure of cancerous tissues to more radicalic stress.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Aged; Catalase; Humans; Middle Aged; Reference Values; Superoxide Dismutase; Urinary Bladder; Urinary Bladder Neoplasms; Xanthine Oxidase

Xanthine oxidase catalyzed mutagenicity of 4-nitrobiphenyl (NBP), a dog-bladder carcinogen, was tested in Ames assay using Salmonella typhimurium TA98 strains. NBP was active as a mutagen in the parent strain TA98 which is proficient in nitroreductase, while it was inactive in the strain TA98NR which is deficient in nitroreductase. However, preincubation of NBP at 37 degrees C with NADH and commercial preparations of xanthine oxidase for 30 min resulted in a dose-dependent increase in the mutagenic activity in TA98NR. Allopurinol blocked the xanthine oxidase catalyzed mutagenicity of NBP in TA98NR and the extent of inhibition was dependent upon the concentration of the inhibitor. Rat-liver and dog-bladder cytosol preparations also enhanced the mutagenic activity of NBP in TA98NR in a dose-dependent manner. In addition, the cytosol-mediated activity was also inhibited by allopurinol, implying that the cytosolic enzyme activity might be due to xanthine oxidase. In vitro enzymatic reduction of NBP using bacterial cell lysates of TA98 and TA98NR revealed the major product of reduction to be 4-aminobiphenyl. The transient intermediates of reduction were not detected during the in vitro incubation. The reduction intermediate N-hydroxylaminobiphenyl showed direct and equal mutagenic activity in both TA98 and TA98NR, in contrast to NBP. These results suggest that N-hydroxylaminobiphenyl is generated during the preincubation of NBP with xanthine oxidase or cytosolic preparations and the former might account for the mutagenicity of NBP. Furthermore, the occurrence of such enzyme(s) in the target tissue for NBP carcinogenesis, support the hypothesis that metabolic activation of the bladder carcinogen NBP could occur within the target organ by virtue of its intrinsic metabolic potential.

Topics: Animals; Biotransformation; Biphenyl Compounds; Cytosol; Dogs; In Vitro Techniques; Microsomes, Liver; Mutagenicity Tests; Rats; Salmonella typhimurium; Urinary Bladder; Urinary Bladder Neoplasms; Xanthine Oxidase

The effects of various chemicals on the development of neoplastic lesions in the urinary bladder were investigated in male F344 rats given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator in their drinking water for 4 weeks. The compounds tested, indomethacin, acemetacin, epsilon-aminocaproic acid (EACA), diphenyl, allopurinol and acetaminophen (AAP), were added to the diet or drinking water for 32 weeks, and all animals were killed at the end of week 36. Of the chemicals tested, only diphenyl significantly increased the incidences and average numbers (per 10 cm basement membrane) of papillary or nodular hyperplasias (PN hyperplasia), papillomas and carcinomas of the urinary bladder over those in animals treated with BBN alone. These findings show that diphenyl is a promoter of urinary bladder carcinogenesis in male F344 rats.

Topics: Acetaminophen; Allopurinol; Aminocaproates; Animals; Biphenyl Compounds; Butylhydroxybutylnitrosamine; Cocarcinogenesis; Hydrogen-Ion Concentration; Indomethacin; Male; Nitrosamines; Rats; Rats, Inbred F344; Sodium; Urinary Bladder; Urinary Bladder Calculi; Urinary Bladder Neoplasms

Summation and synergism in the effects of three tumor promoters on urinary bladder carcinogenesis initiated by a 4-week treatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats were examined. In experiment 1, the sequential administration of sodium saccharin (SS, 5.0%), DL-tryptophan (Tr, 2.0%) and sodium L-ascorbate (SA, 5.0%) in the diet, each for 10 weeks, significantly increased the incidence and the number of bladder tumors over that observed after SS alone or SS followed by Tr. In experiment 2, the simultaneous dietary administration of 2.5% SA, 1.0% butylated hydroxyanisole and 0.01% allopurinol for 32 weeks significantly increased the yield of bladder tumors. Paired combinations of promoters or each of the promoters administered alone were associated with a less pronounced promotive effect than when all three were combined. Thus, it is evident from the results of the present investigation that whatever the mechanisms underlying promotion by the different agents, they are capable of working in an additive fashion, under conditions of summation (consecutive administration) or synergism (simultaneous administration).

Topics: Allopurinol; Animals; Ascorbic Acid; Butylated Hydroxyanisole; Butylhydroxybutylnitrosamine; Drug Synergism; Hyperplasia; Male; Nitrosamines; Rats; Rats, Inbred F344; Saccharin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms

Chemical cystitis and systemic toxic effects limit the therapeutic use of intravesical cytotoxic agents against bladder tumors. In our series 1,000 mg. 5-fluorouracil could be instilled 2 hours daily, 5 days per week for 5 weeks if 100 mg. allopurinol were given 3 times daily simultaneously. After 6 weeks all patients were macroscopically free of tumors. Another instillation was performed because of recurrences within 6 months in 3 patients. This preliminary report of 5 patients with multiple superficial transitional cell bladder tumors shows that a combined treatment of high dose 5-fluorouracil instillation and simultaneous oral allopurinol will abolish temporarily all tumor tissue without signs of general absorption or chemical cystitis. The observation time is too short to predict definitive cure.

Topics: Allopurinol; Carcinoma, Transitional Cell; Drug Therapy, Combination; Fluorouracil; Humans; Neoplasm Recurrence, Local; Time Factors; Urinary Bladder Neoplasms

We studied the capacity of various chemicals to promote urinary bladder cancer in male F344 rats after initiation by N-nitroso-n-butyl-(4-hydroxybutyl)amine (BBN). The rats were given initially 0.01% BBN in the drinking-water for 4 wk and then the test compound in the diet for 34 wk. Effects were judged by measuring the formation of preneoplastic lesions papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder. Administration of 5%, but not 0.5% (w/w) sodium saccharin in the diet significantly increased the incidence and extent of PN hyperplasia. This finding could be related to the induction of cancers in the rat urinary bladder by high levels of saccharin. Sodium ascorbate (5%). DL-tryptophan (5%) and allopurinol (0.02%) also significantly increased the extent of PN hyperplasia in the affected animals, but other test chemicals, such as acetazolamide (0.35%) and quercetin (5%) did not. The results with sodium saccharin and DL-tryptophan were consistent with previous findings and suggest that sodium ascorbate and allopurinol have promoting activities in urinary bladder carcinogenesis in rats. No correlation was found between the extent of crystalluria and promotion of preneoplastic lesions.

Topics: Acetazolamide; Allopurinol; Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Hyperplasia; Male; Neoplasms, Experimental; Nitrosamines; Quercetin; Rats; Rats, Inbred F344; Saccharin; Tryptophan; Urinary Bladder; Urinary Bladder Neoplasms

This study comprises of 48 normal men as control group and 49 patients with various stages of bladder carcinoma. Serum xanthine oxidase and uric acid levels were determined. Assessment in terms of changes of the enzyme xanthine oxidase was carried out prior and after surgery as a short-term follow-up. There was a significant fall of serum xanthine oxidase in patients with bladder carcinoma; it also varied with the stage of cancer.

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Neoplasm Staging; Uric Acid; Urinary Bladder Neoplasms; Xanthine Oxidase

The effects of allopurinol on the induction of bladder cancer by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT), excretion of urinary tryptophan metabolites, hepatic nitroreductase activity, and the acid-soluble thiol content of liver and blood in weanling female Fischer rats were investigated. Four groups of rats were given normal diet or normal diet supplemented with 0.005% allopurinol, 0.188% FANFT, or 0.005% allopurinol-0.188% FANFT. Transitional cell carcinomas appeared in 3 of 30 rats (10%) at 15 weeks and in 7 of 44 rats (16%) at 20 weeks in the FANFT-treated group; the carcinomas appeared in 14 of 35 rats (40%) at 15 weeks and in 27 of 50 rats (54%) at 20 weeks in the FANFT-allopurinol-treated group. Growth rate was not affected by allopurinol and FANFT. Allopurinol alone caused no morphological change in the epithelial cells of the urinary bladder but decreased hepatic cytosol nitroreductase activity. FANFT alone had no effect on hepatic cytosol or microsomal nitroreductase activity but increased hepatic and blood acid-soluble thiol content. FANFT increased the urinary excretion of anthranilic acid glucuronide, kynurenine, acetylkynurenine, and 3-hydroxykynurenine and decreased indican and o-aminohippurate excretion. Allopurinol did not alter the effects of FANFT on the acid-soluble thiol content of liver and blood or the excretion of urinary tryptophan metabolites.

Topics: Allopurinol; Animals; Carcinoma, Transitional Cell; Cytosol; Drug Synergism; FANFT; Female; Liver; Neoplasms, Experimental; Nitrate Reductases; Rats; Sulfhydryl Compounds; Thiazoles; Time Factors; Tryptophan; Urinary Bladder Neoplasms