title: TP53 modulating agent, CP-31398 enhances antitumor effects of ODC inhibitor in mouse model of urinary bladder transitional cell carcinoma.
abstract: Mutations of the tumor suppressor p53 and elevated levels of polyamines are known to play key roles in urothelial tumorigenesis. We investigated the inhibition of polyamines biosynthesis and the restoration of p53 signaling as a possible means of preventing muscle invasive urothelial tumors using DFMO, an ODC-inhibiting agent, and CP-31398 (CP), a p53 stabilizing agent. Transgenic UPII-SV40T male mice at 6weeks age (n=15/group) were fed control diet (AIN-76A) or experimental diets containing DFMO (1000 and 2000 ppm) or 150 ppm CP or both. At 40 weeks of age, all mice were euthanized and urinary bladders were evaluated to determine tumor weight and histopathology. Low-dose DFMO had a moderate significant inhibitory effect on tumor growth (38%, P<0.02) and tumor invasion (23%). High-dose DFMO had a 47% tumor inhibition (P<0.0001) and 40% inhibition tumor invasion. There was no significant difference between 1000 and 2000 ppm doses of DFMO (P>0.05). CP at 150 ppm alone had a strong inhibitory effect on tumor growth by 80% (P<0.0001); however, no effect on tumor invasion was observed. Interestingly, the combination of DFMO (1000 ppm) and CP (150 ppm) led to significant decrease in tumor weight (70%, P<0.0001) and tumor invasion (62.5%; P<0.005). Molecular analysis of the urothelial tumors suggested a modulation of polyamine biosynthesis, proliferation, cell cycle regulators resulting from the use of these agents. These results suggest that targeting two or more pathways could be an effective approach for chemoprevention. A combination of CP and DFMO appears to be a promising strategy for urothelial TCC prevention.
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Department of Urology, NYU Medical Center NY, USA.
authors.forename: Xueru
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Cancer Prevention, Chemoprevention Agent Development Research Group, National Cancer Institute Bethesda, MD, USA.
authors.forename: Vernon
authors.initials: V
authors.lastname: Steele
authors.affiliation: Weill Cornell Medical College, Cornell University USA.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Center for Cancer Prevention and Drug Development, Stephenson Cancer Center, Department of Medicine, Hematology-Oncology Section, University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
keywords: CP-31398; DFMO; Transitional cell carcinoma; UPII-SV40T; chemoprevention; ornithine decarboxylase; polyamines