Breast tissue accumulation of retinamides in a randomized short-term study of fenretinide.
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.
Sabichi
Anita L
AL
Departments of Clinical Cancer Prevention and Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Modiano
Manual R
MR
Lee
J Jack
JJ
Peng
Yei-Mei
YM
Xu
Ming-Jing
MJ
Villar
Hugo
H
Dalton
William S
WS
Lippman
Scott M
SM
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*
D017313:Fenretinide; D014212:Tretinoin; C054441:retinamide