In summary, data in the present study suggest the likely involvement of NO in the initiation, progression, andor promotion of cholangiocarcinoma during inflammatory conditions of the bile ducts.NO and associated reactive oxygen species such as peroxynitrite modify DNA bases and result in direct DNA damage.Concomitantly, nitrosylation of key repair proteins inhibit the repair of the DNA alterations promoting the accumulation of potential oncogenic mutations important in the initiation andor progression of this cancer.Based on this information, we speculate that iNOS inhibitors targeted to cholangiocytes could potentially have a chemopreventive role in patients with chronic inflammatory cholangiopathies, such as patients with primary sclerosing cholangitis.Gastroenterology. Inducible nitric oxide synthase expression in chronic viral hepatitis: Evidence for a virusinduced geneupregulation.Expression of a novel activation antigen on intrahepatic CD T lymphocytes in viral chronic active hepatitis.Hepatology. Science. Gut. Hepatology. Carcinogenesis. Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on September. American Association for Cancer Research. We now show that DNA damage is able to induce senescence in tumor cells expressing wildtype p.We also show that cytotoxics are capable of inducing senescence in tumor tissue in vivo.Thus, like apoptosis, senescence appears to be a pinduced cellular response to DNA damage and an important factor in determining treatment outcome.Since then, replicative senescence has been shown in various mammalian tissues in culture and in vivo. Contrary to normal somatic cells, most tumors have extended or infinite life spans.Cellular and viral oncogenes, or the loss of tumor suppressors, are involved in the transformation and immortalization of primary cells.One of the genes transcriptionally activated by p is the p gene. There is evidence that the transcriptional activity of p also plays an important role in the induction of cellular senescence, most likely via transactivation of the p gene. Consistent with this, tetracyclineinduced expression of p in human bladder cells induced senescence. We have previously reported that human colon and ovarian carcinoma cells lacking or expressing mutant p treated with topoisomerase inhibitors undergo rapid apoptosis after SG arrest.However, in carcinoma cells expressing wildtype p, the response was characterized mainly by prolonged cell cycle arrest. Topoisomerase inhibitors are commonly used anticancer drugs, and like most cytotoxics are used to induce DNA damage in tumor cells, activating p and leading to cell cycle arrest or apoptosis. It has also been shown that these drugs are potent inducers of a reversible senescencelike state in normal human fibroblasts. In the present study we investigated whether topoisomerase inhibitors were able to induce senescence in colon, ovarian, and breast adenocarcinoma cell lines expressing wildtype p.These cells had the morphological and biochemical characteristics of cellular senescence.When cells were recultured in drugfree medium, the p and p levels decreased to normal.Furthermore, isogenic cell line pairs either lacking p or p were unable to induce the senescence program in contrast to the parental cell line after treatment.Thus, senescence may not be just a characteristic of aging cells, but like the apoptotic pathway is a pinduced cellular response to DNA damage that acts to prevent the proliferation of damaged cells.