retinamide and Urinary-Bladder-Neoplasms

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.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Transitional Cell; Cell Division; Fenretinide; Humans; Retinoids; Tretinoin; Tumor Cells, Cultured; Urinary Bladder Neoplasms

The model of precancerous lesions of the bladder in rats was induced by N-butyl-(4-hydroxybutyl) nitrosamide (BBN). The animals were randomly divided into the following 3 groups: 1) given Antitumor-B (Chinese herbs); 2) given 4-ethoxycarbophenylretinamide (Retinamide); and 3) control. After treatment for 13 months the rats were killed for pathomorphological examination of the bladder. The results showed that the incidence of bladder cancer in group 1 and 2 was reduced by 90.7% (P < 0.01) and 75.0% (P < 0.01) respectively after treatment as compared with the control group. Our results provide a useful reference for clinical trial in the prevention of bladder cancer recurrence by using antitumor-B and Retinamide.

Topics: Animals; Antineoplastic Agents, Phytogenic; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Precancerous Conditions; Rats; Rats, Wistar; Tretinoin; Urinary Bladder Neoplasms