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 effect of 4-HPR in breast cells is mediated by 4-HPR directly or through one of its metabolites. In this report, we investigated in vivo and in vitro effects of 4-HPR on three different breast carcinoma cells and two different melanoma cell lines. In vitro, the growth of all three breast carcinoma cell lines was inhibited by 4-HPR. Only one of two melanoma cell lines (UISO-Mel-1) showed growth inhibition to 4-HPR. The cell 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 growth of UISO-BCA-1 xenografts in female athymic mice, but had no effect on UISO-Mel-6 xenografts. Metabolism investigations of the 4-HPR-sensitive and insensitive cell lines indicated that N-[4-methoxyphenyl]retinamide (4-MPR), the major metabolite of 4-HPR, was detected only in cells sensitive to 4-HPR. Further in vitro studies with 4-MPR suggested that it is not an active metabolite of 4-HPR as it failed to inhibit growth of 4-HPR-resistant UISO-Mel-6 cells, and showed no dose-dependent inhibition of 4-HPR-sensitive breast carcinoma and melanoma cell lines. Our results in the present study indicate that, although 4-MPR is not 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.