The metabolite N-4-methoxyphenylretinamide is a major determinant of fenretinide induced decline of plasma insulin-like growth factor-1

Abstract

INSULIN-LIKE GROWTH factor (IGF-l), a potent mitogen for breast cancer cells, has been implicated in the promotional steps of breast carcinogenesis [I]. We have recently shown that the administration of the synthetic retinoid, fenretinide (N(4-hydroxyphenyl)retinamide, 4-HPR), induces a significant decline in circulating levels of IGF-1 in breast cancer patients, which was more pronounced in younger women [2]. It is possible that the decrease of available IGF-1 in plasma might represent at least one of the mechanisms through which the retinoid interferes with the carcinogenic process. This study augments our previous work in that it endeavours to investigate the effects of plasma concentrations of 4-HPR and of its major metabolite N-(4-methoxyphenyl)retinamide (CMPR) on plasma IGF- 1. The 20 stage I (T,.,N,) breast cancer patients enrolled in the study were part of a large randornised trial of contralateral breast cancer chemoprevention with 4-HPR [3]. All patients had been randomised to receive 4-HPR (R.W. Johnson Pharmaceutical Institute, Springhouse, Pennsylvania, U.S.A.) 200 mg daily, orally for 5 years with a monthly 3-day drug holiday. Median age was 53.5 years (range 39-67) and mean body mass index (BMI), expressed as weight (kg) divided by squared height (m2), was 24.32 ? 0.6. Sixteen patients were postmenopausal and 4 premenopausal. IGF-1 levels were measured by radioimmunoassay on plasma obtained at randomisation and after a mean interval of 11 & 0.6 months, as previously described [2]. At baseline, plasma IGF-1 levels (mean + S.E.) were 154.8 + 11.4 rig/ml and decreased to 132.8 2 8.7 nglml after treatment (P=O.O06, Student t-test). Plasma levels of 4-HPR and 4-MPR were determined by highperformance liquid chromatography (HPLC), on blood samples obtained after a median time on treatment of 32 months (range U5), as previously described [4]. Since plasma levels of the drug and the metabolite have been shown to be stable during