The expression of many genes is altered in colon cancer, but the roles of these genes in carcinogenesis are unclear. Using real-time quantitative PCR, we demonstrated that several genes previously implicated in human colon cancer undergo altered expression in the APC min mouse adenomatous polyp, a precursor of cancer, as well as in normal-appearing surrounding mucosa. The five genes that were most highly up-regulated in mouse polyp were also significantly up-regulated in polyp-free colon mucosa. Similar changes occurred in morphologically normal mucosa of surgical sections taken from human cancer patients, frequently extending to the margins. Thus, morphologically normal colon mucosa in APC min mice and in human cancer patients is not metabolically normal. Altered gene expression in this tissue does not appear to result from a field effect because there was no correlation between extent of altered regulation and distance from polyp or tumor. Our data suggest that alterations of expression levels of these genes may be an early event in carcinogenesis and a marker of risk for the development of colon cancer.
High response rates have been reported with hepatic intra-arterial infusions of floxuridine in patients having colorectal carcinoma metastatic to the liver. The major toxicity of this therapy has been described as "chemical hepatitis." In a randomized trial of intravenous v intra-arterial floxuridine, we observed that all 35 patients receiving intra-arterial therapy developed significant increases in alkaline phosphatase and, in some cases, serum glutamic oxaloacetic transminase and/or bilirubin. Seven patients receiving intra-arterial therapy were studied with cholangiography which, in all cases, demonstrated sclerosis of the intrahepatic and/or extrahepatic bile ducts. In addition, liver biopsies showed cholestasis and pericholangitis with minimal hepatocyte damage. These findings suggest that "biliary sclerosis" rather than "chemical hepatitis" is the predominant toxicity associated with hepatic intra-arterial infusions of floxuridine.
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