Abstract 3690: p53 stabilizing agent CP-31398 prevents urinary bladder tumor growth and invasion in transgenic UPII-SV40T mice.

Abstract

Abstract The United States will have approximately 73,510 new cases of bladder cancer in 2012 with 14,880 deaths. More than 50% of the invasive (lamina and muscularis) bladder tumors have mutations in p53 and/or pRB. p53 appears to play a major role in the etiology of human bladder cancer, particularly in the high grade invasive type. Structural and functional defects in p53 are found in majority of human transitional cell carcinomas (TCC). The high prevalence of bladder cancer and the frequency of tumor recurrence make it an important target for chemoprevention. In UPII-SV40T transgenic mice, induced bladder TCC bears strong resemblance to that of human TCC in phenotype and in the mode of progression. In the present study, we determined the chemopreventive efficacy of a p53 stabilizing agent, CP-31398, using transgenic UPII-SV40T mouse model. After genotyping, six-week old UPII-SV40T mice (n=32/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm CP-31398 for ∼34 weeks. Progression of bladder cancer was monitored by MRI imaging. At 40 weeks of age, all mice were euthanized; urinary bladders were collected to determine weights, tumor incidence and multiplicity; and histopathology. There was a significant increase in bladder weights of transgenic vs. wild type mice (male 140.2 mg vs. 27.3 mg, p<0.0001; female 34.2 mg vs, 14.8 mg p<0.0001, respectively). A significant decrease in the tumor growth as evidenced by decreased bladder weights (by 52-65%, p<0.000 in males; by 32 %, p<0.001 in females) was observed in CP-31398 treated mice. Invasive papillary TCC incidence was 100 % in transgenic mice fed with control diet. The mice exposed to 150 and 300 ppm CP-31398 showed dose dependent inhibition (29%, p<0.01; 57%, p<0.005) of invasive TCC with 28% and 53% carcinoma In situ, respectively, suggesting suppression of invasive tumor growth. Kidney abnormalities like ureter obstruction and nephrohydrosis were observed in almost all control mice but significantly less frequent in CP-31398-fed mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax) with a decrease in angiogenic markers (CD31 and VEGF) in transgenic mice fed with CP-31398. These results suggest that p53 modulating agents can serve as potential chemopreventive for bladder TCC. (Supported in part by NCI-CN53300) Citation Format: Venkateshwar Madka, Yuting Zhang, Qian Li, Altaf Mohammed, Stan Lightfoot, Wu Re Xue, Levy Kopelovich, Chinthalapally V. Rao. p53 stabilizing agent CP-31398 prevents urinary bladder tumor growth and invasion in transgenic UPII-SV40T mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3690. doi:10.1158/1538-7445.AM2013-3690