Commentary on "tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl) nitrosamine as the basis for urothelial cell carcinogenesis." He Z, Kosinska W, Zhao ZL, Wu XR, Guttenplan JB, Department of Basic Science, New York University Dental College, NY, USA.: Mutat Res 2012;742(1-2):92-5 [Epub 2011 Dec 4].

Bladder cancer is one of the few cancers that have been linked to carcinogens in the environment and tobacco smoke. Of the carcinogens tested in mouse chemical carcinogenesis models, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is one that reproducibly causes high-grade, invasive cancers in the urinary bladder, but not in any other tissues. However, the basis for such a high-level tissue-specificity has not been explored. Using mutagenesis in lacI (Big Blue™) mice, we show here that BBN is a potent mutagen and it causes high-level of mutagenesis specifically in the epithelial cells (urothelial) of the urinary bladder. After a 2-6-week treatment of 0.05% BBN in the drinking water, mutagenesis in urothelial cells of male and female mice was about two orders of magnitude greater than the spontaneous mutation background. In contrast, mutagenesis in smooth muscle cells of the urinary bladder was about five times lower than in urothelial tissue. No appreciable increase in mutagenesis was observed in kidney, ureter, liver or forestomach. In lacI (Big Blue™) rats, BBN mutagenesis was also elevated in urothelial cells, albeit not nearly as profoundly as in mice. This provides a potential explanation as to why rats are less prone than mice to the formation of aggressive form of bladder cancer induced by BBN. Our results suggest that the propensity to BBN-triggered mutagenesis of urothelial cells underlies its heightened susceptibility to this carcinogen and that mutagenesis induced by BBN represents a novel model for initiation of bladder carcinogenesis.

Anti-tumor effect of novel cationic biomaterials in prostate cancer.

BACKGROUND: Tumor cells expressing excessive anionic-charged sialic acid can be potentially targeted by cationic polymers which may inhibit tumor growth. In the present study, three new families of cationic polymers were synthesized to assess their effects on prostate cancer cells. MATERIALS AND METHODS: Cationic polymers effects on PC3 prostate cancer cells and normal prostate epithelial cell (RWPE-1) were assessed using cell viability, DNA fragmentation, apoptosis assays and confocal microscopy. RESULTS: The dextran-based polymer (Dex-PA-3X) (40 µg/ml) and the vinyl-based PolyAETA (5 µg/ml) induced a significant reduction in cell viability in PC3 cells (85% and 50%, respectively; p<0.05) in comparison to RWPE-1 cells. Furthermore, Dex-PA-3X induced a 50%, and PolyAETA induced a 35% increase in cell death in PC3 cells compared to RWPE-1 cells measured by DNA fragmentation assay. Lower concentrations of both polymers induced apoptosis while higher concentrations induced both apoptosis and necrosis by immunostaining. Confocal microscopy indicated the localization of Dex-PA in the cytoplasm of PC3 but not RWPE-1 cells, while PolyAETA was seen in both PC3 and RWPE-1 cells, but at lower intensity in RWPE-1 cells. CONCLUSION: The newly-synthesized cationic polymers Dex-PA-3X and PolyAETA selectively bind to, reduce viability and induce cell apoptosis in prostate cancer cells, suggesting that targeting negatively-charged tumor cells could be a novel strategy to treat prostate cancer.