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Suppression of Familial Adenomatous Polyposis by CP-31398, a TP53 Modulator, in APC^min/+ Mice

¹ Department of Medicine, Hem-Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and ² Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Chinthalapally V. Rao, Department of Medicine, Hem-Onc Section, University of Oklahoma Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104. Phone: 405-271-3224; Fax: 405-271-3225; E-mail: cv-rao{at}ouhsc.edu.

Key Words: Colon cancer • Chemoprevention • Tumor suppressor proteins • p53 modulators • Apoptosis

p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APC^min (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP-31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21^WAF1/CIP, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APC^min/+ mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation. [Cancer Res 2008;68(18):7670–5]