Effects of novel phenylretinamides on cell growth and apoptosis in bladdercancer

Superficial bladder cancer is a major target for chemoprevention. Retinoids are important modulators of epithelial differentiation and proliferation a nd are effective in the treatment and prevention of several epithelial canc ers. One class of compounds, the retinamides, is structurally similar to ot her retinoids but have the added feature of being potent apoptosis inducers . Among these, fenretinide (N-[4-hydroxyphenyl]retinamide), or 4HPR, has pr omise for bladder cancer chemoprevention and is currently under Phase III s tudy in this setting. In addition to 4HPR, there are several new structural ly related phenylretinamides bearing hydroxyl, carboxyl, or methoxyl residu es on carbons 2, 3, and 4 of the terminal phenylamine ring [designated N-(2 -hydroxyphenyl)retinamide, N-(3-hydroxyphenyl)retinamide, N-(2-carboxypheny l)retinamide, N-(3-carboxyphenyl)retinamide, N-(4-carboxyphenyl)retinamide, and N-(4-methoxyphenyl) retinamide, respectively], The objective of this s tudy was to compare the growth inhibitory and apoptotic effects of these ph enylretinamides with 4HPR in human bladder transitional cell cancer-derived cell lines of varying histological grade (RT4, grade 1; UM-UC9 and UM-UC10 , grade 3; and UM-UC14, grade 4) by cell counting, cell cycle fluorescence- activated cell sorter analysis and a dual stain apoptosis assay. All of the seven phenylretinamides reduced cell number, altered the cell cycle distri bution, and induced apoptosis when administered at a concentration of 10 mu M, which is within the pharmacologically achievable range. Although the rel ative potencies of the phenylretinamides varied depending on the cell line, N-(3-hydroxy phenyl)retinamide was the most active with significantly grea ter growth inhibition than 4HPR in all of the four cell lines. These in vit ro findings warrant further study of these novel phenylretinamides, which m ay have potential as preventive or therapeutic agents in transitional cell cancer.