METABOLISM OF N-[4-HYDROXYPHENYL]RETINAMIDE (4-HPR) TO N-[4-METHOXYPHENYL]RETINAMIDE (4-MPR) MAY SERVE AS A BIOMARKER FOR ITS EFFICACY AGAINST HUMAN BREAST-CANCER AND MELANOMA-CELLS

A clinical trial of N-[4-hydroxyphenyl]retinamide (4-HPR) has been in progress for the past 4 years to evaluate its role in chemoprevention of breast cancer. However, it is currently not known whether the effec t of 4-HPR in breast cells is mediated by 4-HPR directly or through on e of its metabolites. In this report, we investigated in vivo and in v itro effects of 4-HPR on three different breast carcinoma cells and tw o different melanoma cell lines. In vitro, the growth of all three bre ast carcinoma cell lines was inhibited by 4-HPR. Only one of two melan oma cell lines (UISO-Mel-1) showed growth inhibition to 4-HPR. The cel l lines sensitive to 4-HPR in vitro also showed inhibition to 4-HPR in a xenograft model. Dietary 4-HPR (0.5 mmol/kg diet) reduced the growt h of UISO-BCA-1 xenografts in female athymic mice, but had no effect o n UISO-Mel-6 xenografts. Metabolism investigations of the 4-HPR-sensit ive and insensitive cell Lines indicated that N-[4-methoxyphenyl]retin amide (4-MPR), the major metabolite of 4-HPR, was detected only in cel ls sensitive to 4-HPR. Further in vitro studies with 4-MPR suggested t hat it is not an active metabolite of 4-HPR as it failed to inhibit gr owth of 4-HPR-resistant UISO-Mel-6 cells, and showed no dose-dependent inhibition of 4-HPR-sensitive breast carcinoma and melanoma cell line s. Our results in the present study indicate that, although 4-MPR is n ot an active metabolite of 4-HPR, detection of this metabolite in the malignant cells may serve as an indirect biomarker to predict response of cells to 4-HPR. (C) 1998 Elsevier Science Ltd. All rights reserved .