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.

Abstract

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.

• Authors: R R Mehta, M E Hawthorne, J M Graves, R G Mehta
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 34 Issue 6 Pg. 902-7 (May 1998) ISSN: 0959-8049 [Print] England
• PMID: 9797705 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Fenretinide

Topics

• Animals
• Antineoplastic Agents (metabolism, therapeutic use)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Transformation, Neoplastic
• Dietary Supplements
• Female
• Fenretinide (metabolism, therapeutic use)
• Humans
• Melanoma (drug therapy, metabolism)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Skin Neoplasms (drug therapy, metabolism)
• Tumor Cells, Cultured