sodium-bicarbonate and Cocarcinogenesis

The effect of terephthalic acid (TPA) on urinary bladder carcinogenesis was examined. Male Wistar rats were initiated by injection of N-Methyl-N-Nitrosourea (MNU) (20 mg/kg b.w. ip) twice a week for 4 weeks, then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO3) or 1% TPA for the next 22 weeks, and then euthanized. 5% TPA treatment induced a high incidence of urinary bladder calculi and a large amount of precipitate. Though 5% TPA plus 4% Sodium bicarbonate (NaHCO3) and 1% TPA treatment did not induce urinary bladder calculi formation, they resulted in a moderate increase in urinary precipitate. Histological examination of urinary bladder revealed that MNU-5% TPA treatment resulted in a higher incidence of simple hyperplasia, papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer than MNU control. MNU-5% TPA plus 4% Sodium bicarbonate (NaHCO3) and 1% TPA treatment increased slightly the incidence of simple hyperplasia and PN hyperplasia (not statistically significant). The major elements of the precipitate are phosphorus, potassium, sulfur, chloride, calcium and TPA. The present study indicated that the calculi induced by TPA had a strong promoting activity on urinary bladder carcinogenesis and the precipitate containing calcium terephthalate (CaTPA) may also have weak promoting activity on urinary bladder carcinogenesis.

Topics: Animals; Carcinogenicity Tests; Cocarcinogenesis; Dose-Response Relationship, Drug; Hyperplasia; Male; Methylnitrosourea; Microscopy, Electron, Scanning; Phthalic Acids; Rats; Rats, Wistar; Sodium Bicarbonate; Urinalysis; Urinary Bladder; Urinary Bladder Calculi; Urinary Bladder Neoplasms

Urinary bladder hyperplasia associated with terephthalic acid (TPA) treatment was examined with concomitant use of sodium bicarbonate (NaHCO3) or hydrochlorothiazide to allow assessment of the relationship among bladder stones, epithelial hyperplasia, and corresponding cell cycle checkpoint gene expression in Sprague-Dawley (SD) rat.. A total of 112 weanling male SD rats that divided between six groups were given basal diet (control), diets containing 5% TPA or in combination with either 4% sodium NaHCO3 or 0.02% hydrochlorothiazide. After 90-day feeding, bladder samples were collected for histopathological diagnoses, and immunohistochemical method was used to characterize the expression of p16Ink4a cyclin D1, CDK4, EGFr and cyclin E in relation to that of proliferating cell nuclear antigen (PCNA).. In TPA treatment groups, bladder stone incidence was 40% (21/52) with 14 cases of proliferative bladder. In control and other groups, neither stone nor epithelial cell proliferation was diagnosed. PCNA-positive focal hyperplasic lesions involved all epithelial layers. Overexpressions of cyclin D1, CDK4, EGFr are found in the corresponding lesion. p16Ink4a nuclear staining reduced in proliferative bladders especially with a great quantity of stone. In addition, no positive expression was detected on cyclin E.. The present study provides a strong evidence of a link between induction of bladder hyperplasia, deregulation of the p16Ink4a-cyclin D1/CDK4 pathway, and abnormal EGFr mediated signal transduction pathway.

Topics: Animals; Cell Division; Cocarcinogenesis; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; Epithelial Cells; ErbB Receptors; Free Radical Scavengers; G1 Phase; Hydrochlorothiazide; Hyperplasia; Immunohistochemistry; Male; Phthalic Acids; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins; Random Allocation; Rats; Rats, Sprague-Dawley; S Phase; Sodium Bicarbonate; Urinary Bladder; Urinary Bladder Calculi

The study was designed to investigate whether sodium bicarbonate (NaHCO3) and/or L-ascorbic acid (AsA) promote urinary bladder carcinogenesis in male ODS/Shi-od/od (ODS) rats, which, unlike male F344 rats, are resistant to sodium L-ascorbate (Na-AsA)-promoting effects. Whereas F344 rats can synthesize AsA and alpha 2 mu-globulin (A2 mu-G), only A2 mu-G in produced in ODS rats. The two strains were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 2 wk and then were fed basal CA-1 diet supplemented with 3% NaHCO3 plus 5% AsA (NaHCO3 + AsA), 3% NaHCO3, 5% AsA, or no chemicals for 32 wk. ODS rats given BBN-NaHCO3 or BBN-(NaHCO3 + AsA) had only a few small carcinomas in the urinary bladder, like those receiving BBN alone or BBN-AsA. In contrast, F344 rats administered BBN-NaHCO3 or BBN-(NaHCO3 + AsA) had many more, larger, carcinoma than animals of the same strain given BBN alone or BBN-AsA. AsA alone did not have any effect in either strain. Administration of NaHCO3 alone or NaHCO3 + AsA was associated with significant elevation of urinary pH and Na+ concentration to the same extent in both strains but, again, AsA alone was without effect. NaHCO3 + AsA and AsA alone increased the urinary concentration of total ascorbic acid in both strains but the observed levels wer lower in ODS rats. The results indicate that ODS rats are resistant to the modifying effects of NaHCO3 and/or AsA on two-stage urinary bladder carcinogenesis, and thus that the susceptibility to the promotional activity of sodium-salt-type compounds may be regulated by factors other than A2 mu-G-synthesizing ability and urinary levels of pH, Na+ and total ascorbic acid.

Topics: alpha-Macroglobulins; Animals; Ascorbic Acid; Body Weight; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma; Cocarcinogenesis; Drug Combinations; Eating; Hydrogen-Ion Concentration; Male; Rats; Rats, Inbred F344; Rats, Mutant Strains; Sodium; Sodium Bicarbonate; Urinalysis; Urinary Bladder Neoplasms

The promoting activities of NaHCO3 and NaCl in two-stage urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were investigated. Male F344 rats were given 0.05% BBN in their drinking water for 4 weeks and then treated with basal diet containing either 3% NaHCO3, 1% NaCl or no added chemical for 32 weeks. NaHCO3 significantly increased the induction of neoplastic and preneoplastic lesions of the urinary bladder, whereas NaCl did not. NaHCO3 produced elevation of urinary pH and urinary Na+ concentration. NaCl increased urinary Na+ concentration without the elevation of urinary pH. In an additional experiment, DNA synthesis in the urinary bladder epithelium was significantly increased in the groups given 3% NaHCO3, 5% sodium L-ascorbate and 1% NaCl. These results confirm that urinary components, increase in urinary pH and Na+ concentration play an important role in the promotion of urinary bladder carcinogenesis in rats.

Topics: Animals; Bicarbonates; Butylhydroxybutylnitrosamine; Cocarcinogenesis; DNA; Hydrogen-Ion Concentration; Osmolar Concentration; Rats; Sodium; Sodium Bicarbonate; Urinary Bladder Neoplasms; Urine