Superficial
bladder cancer is a major target for
chemoprevention.
Retinoids are important modulators of epithelial differentiation and proliferation and are effective in the treatment and prevention of several epithelial
cancers. One class of compounds, the retinamides, is structurally similar to other
retinoids but have the added feature of being potent apoptosis inducers. Among these,
fenretinide (N-[4-hydroxyphenyl]
retinamide), or 4HPR, has promise for
bladder cancer chemoprevention and is currently under Phase III study in this setting. In addition to 4HPR, there are several new structurally related phenylretinamides bearing
hydroxyl, carboxyl, or methoxyl residues on carbons 2, 3, and 4 of the terminal
phenylamine ring [designated
N-(2-hydroxyphenyl)retinamide, N-(3-hydroxyphenyl)retin
amide, N-(2-carboxyphenyl)retin-
amide, N-(3-carboxyphenyl)retin
amide, N-(4-carboxy- phenyl)retinamide, and
N-(4-methoxyphenyl)retinamide, respectively]. The objective of this study was to compare the growth inhibitory and apoptotic effects of these phenylretinamides 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 distribution, and induced apoptosis when administered at a concentration of 10 microM, which is within the pharmacologically achievable range. Although the relative potencies of the phenylretinamides varied depending on the cell line, N-(3-hydroxy phenyl)retin-
amide was the most active with significantly greater growth inhibition than 4HPR in all of the four cell lines. These in vitro findings warrant further study of these novel phenylretinamides, which may have potential as preventive or therapeutic agents in transitional cell
cancer.