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Effects of novel phenylretinamides on cell growth and apoptosis in bladder cancer.

Abstract
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.
AuthorsJ L Clifford, A L Sabichi, C Zou, X Yang, V E Steele, G J Kelloff, R Lotan, S M Lippman
JournalCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 10 Issue 4 Pg. 391-5 (Apr 2001) ISSN: 1055-9965 [Print] United States
PMID11319181 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Anticarcinogenic Agents
  • Antineoplastic Agents
  • Retinoids
  • Fenretinide
  • retinamide
  • Tretinoin
Topics
  • Anticarcinogenic Agents (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Apoptosis (drug effects)
  • Carcinoma, Transitional Cell (pathology)
  • Cell Division (drug effects)
  • Fenretinide (pharmacology)
  • Humans
  • Retinoids (pharmacology)
  • Tretinoin (analogs & derivatives, pharmacology)
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms (pathology)

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