Nongenotoxic bladder carcinogens that form bladder calculi have been concluded to be of low carcinogenic risk to humans because bladder stones would be expelled or surgically removed before they had a chance to exert their carcinogenic effect. It is the aim of this report to examine the possible contribution of indomethacin to the carcinogenic risk posed by nongenotoxic bladder carcinogens that cause bladder stones. Indomethacin may act as a tumor promoter in the bladder by interfering with the synthesis of prostaglandins. Prostaglandins have a cytoprotective function in the gastric mucosa and possibly also in the urinary bladder. Diminished cytoprotection may be implicated in bladder carcinogenesis as β-naphthylamine, a human bladder carcinogen, also inhibits prostaglandin synthesis in vitro. The presence of other tumor promoters in the bladder may further ensure that tumors would be formed even if bladder stones were expelled. People who are exposed to nongenotoxic bladder carcinogens that are present in the environment and that form bladder stones, therefore, may be at an increased risk for developing bladder cancer if they are also exposed to tumor promoters, such as indomethacin.
A mechanistic hypothesis was formulated for the possible contribution of indomethacin to the carcinogenicity of nongenotoxic bladder carcinogens that form bladder stones.
It has been suggested that the mechanism of carcinogenicity for nongenotoxic bladder carcinogens that form bladder calculi includes an initiation phase caused by mutagens in the urine and a promotion phase caused by irritation, inflammation, and resulting cell proliferation produced by bladder calculi (Clayson et al., 1970; Rodent Bladder Carcinogenesis Working Group, 1995). A threshold-dependent mechanism of carcinogenicity for nongenotoxic bladder carcinogens that form bladder calculi therefore was proposed (Rodent Bladder Carcinogenesis Working Group, 1995).
Dr. Harry A. Milman, is an international authority in Toxicology, Carcinogenesis (e.g., cancer causation), Pharmacology, and Pharmacy Standard of Care with over 40 years experience at the US National Cancer Institute of the National Institutes of Health, the US Environmental Protection Agency, the US Public Health Service, and as a Consulting Toxicologist.
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