Other Agents under Trial

Other agents under investigation in colorectal chemoprevention include difluoromethylornithine (DFMO), which irreversibly inhibits ornithine decarboxylase and blocks cell proliferation. Ursodeoxy-cholic acid reduces the concentration of the secondary bile acid deoxycholic acid in the colon and affects arachidonic acid metabolism [9-11]. 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitors are usually used in the setting of lowering cholesterol but also have antioxidant anti-inflammatory properties and inhibit cell proliferation [12]. Preclinical work in mutant APC murine models have shown that sulin-dac in combination with EGFR inhibitor EKI-785 can decrease intestinal polyps [13]. Almost one-half the mice treated with the combination agents did not develop polyps. With the recent success of beva-cizumab, an antibody to the VEGF-receptor in metastatic colorectal cancer, and cetuximab, an antibody to EGFR, further strategies will be applied to prevention.

The continued study of immunology, tumour biology and natural history through controlled trials focusing not only on efficacy endpoints but also on biological markers in tissue and serum will help develop detailed risk models. Chemopreventive agents appear thus far to have efficacy in several tumour types, and we hope to define their future role in treating and preventing other cancers in high-risk individuals.

Advances in delaying the development of colorec-tal carcinoma have been shown in patients with FAP with celecoxib treatment. Current and future trials using celecoxib alone or in combination with chemotherapy and other biological therapies are targeting several cohorts including children with APC mutations, patients with FAP, HNPCC, prior colorectal adenoma, or prior history of sporadic adenomas [14]. The use of celecoxib in the prevention of polyps has resulted in continued efforts to define a high-risk population and to implement a chemopreventive agent in the treatment of cancer. With regard to aspirin use in the prevention of colon adenomas, two large randomised, placebo-controlled trials showed benefit. However, although the Aspirin/Folate Polyp Prevention Study and the Colorectal Adenoma Prevention Study reported positive results, a certain percentage of patients receiving aspirin intervention still developed colon adenomas. This suggests that aspirin use cannot be a substitute for colon surveillance and that further studies are necessary for effective colon cancer chemoprevention.

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