title: Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide.
abstract: OBJECTIVE
  The synthetic retinoid N-(4-hydroxyphenyl)retinamide [4-HPR (or fenretinide)] has preclinical and clinical preventive activity in breast carcinogenesis. 4-HPR and its metabolites have been shown to accumulate in the mammary tissue of rodents. We assessed levels of 4-HPR and its major metabolite, N-(4-methoxyphenyl)retinamide (4-MPR), in plasma and in normal and neoplastic breast tissue obtained from women treated with 4-HPR.
  
  
  METHODS
  We randomly assigned 14 women with suspected or very recently diagnosed breast cancer to receive 100, 200, or 300 mg of 4-HPR daily for 3-12 days before scheduled biopsy, lumpectomy, or mastectomy. Using high-performance liquid chromatography, we measured post-4-HPR-treatment concentrations of 4-HPR and 4-MPR in plasma and breast tissue obtained during surgery.
  
  
  RESULTS
  Breast tissue and plasma retinamide (4-HPR plus 4-MPR) concentrations increased significantly with short-term oral administration of 4-HPR. Retinamide levels increased in a linear and dose-related fashion in plasma, whereas they peaked and plateaued at 200 mg/day in breast tissue. The total retinamide concentration in breast tissue exceeded that in plasma at each 4-HPR dose. The highest mean tissue:plasma retinamide ratios were achieved at 200 mg/day: 639.5 +/- 253.8 to 190.6 +/- 91.9 ng/ml (4.8:1) for 4-HPR and 594.4 +/- 201.9 to 130.5 +/- 37.8 ng/ml (6.6:1) for 4-MPR. Plasma retinol levels decreased in association with increasing 4-HPR doses. Two patients experienced grade 1 toxicity at the 300 mg/day dose.
  
  
  CONCLUSIONS
  These findings indicate that retinamides preferentially accumulate in human breast tissue (versus plasma). 4-HPR tissue concentrations at 200 mg/d were equivalent to those that inhibit growth and induce apoptosis of breast cancer cells in vitro. Previous clinical and correlative laboratory results suggest that 4-HPR may reduce risk in premenopausal women, who are more prone (than are postmenopausal women) to estrogen receptor (ER)-negative breast cancer development. The present results and previous data (including in vitro 4-HPR activity against ER-negative breast cancer) support further study of 4-HPR in the setting of premenopausal/ER-negative breast cancer prevention.
authors.affiliation: Departments of Clinical Cancer Prevention and Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Anita L
authors.initials: AL
authors.lastname: Sabichi
authors.forename: Manual R
authors.initials: MR
authors.lastname: Modiano
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Yei-Mei
authors.initials: YM
authors.lastname: Peng
authors.forename: Ming-Jing
authors.initials: MJ
authors.lastname: Xu
authors.forename: Hugo
authors.initials: H
authors.lastname: Villar
authors.forename: William S
authors.initials: WS
authors.lastname: Dalton
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D017209:Apoptosis; D001940:Breast / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D017313:Fenretinide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D008875:Middle Aged; D011897:Random Allocation; D013997:Time Factors; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D017313:Fenretinide; D014212:Tretinoin; C054441:retinamide