Fenretinide (HPR) is a synthetic
retinoid which has been shown to cause a reduction in the incidence of
carcinogen-induced epithelial
tumors in experimental animals, and it has been chosen to be tested as a chemopreventive agent in humans. A study on plasma concentrations of HPR, of its metabolite
N-(4-methoxyphenyl)retinamide (MPR), and on its effects on endogenous
retinol was performed in groups of 14 to 18
breast cancer patients who received p.o. daily doses of placebo or 100, 200, and 300 mg of HPR for 6 mo and subsequently 200 mg for an additional 6 mo. After the first 5 mo of treatment, there was a linear relationship between doses of HPR administered and HPR, MPR, and
retinol levels. HPR and MPR levels increased with the increase in dose, whereas
retinol levels decreased, and the reduction was statistically significant compared with the placebo group after all the doses tested.
Plasma retinol binding proteins (RBP) decreased proportionally to
retinol (r = 0.96). The effect of HPR on
retinol and RBP occurred early, since
retinol and RBP levels had already been decreased, compared with the initial levels, by 38% and 26%, respectively, 24 h after a 200-mg HPR dose. After 12 mo of treatment, in patients treated with 200 mg daily, the dose chosen for a chemopreventive trial, HPR and
retinol levels were similar to those found at 5 mo, suggesting no
drug accumulation and no further
retinol reduction, whereas MPR levels were higher. Following interruption of treatment, as HPR decreased,
retinol increased with a linear relationship between log levels (r = 0.78); after about 50 days, HPR was present in trace amounts, and
retinol levels were in the range of those of the placebo group. These data show that HPR treatment lowers
retinol and RBP plasma concentrations. This effect is related to HPR levels and is reversible on cessation of HPR administration.