Time course of fenretinide-induced modulation of circulating insulin-like growth factor (IGF)-I, IGF-II and IGFBP-3 in a bladder cancer chemoprevention trial

The insulin-like growth factor (IGF) system is widely involved in human car cinogenesis. A significant association be tween high circulating IGF-I conc entrations and an increased risk of lung, colon, prostate and pre menopausa l breast cancer has recently been reported. Lowering plasma IGF-I may thus represent an attractive strategy to be pursued for chemopreventive purposes . We have previously shown that the synthetic retinoid fenretinide (4-HPR) lowers plasma IGF-I in pre-menopausal breast cancer patients. We investigat ed the effect of fenretinide on circulating IGF-I, IGF-II and IGFBP-3 measu red at yearly intervals during the 2-year treatment period and one year aft er treatment discontinuation in a predominantly male population of patients with superficial bladder cancer. Repeated measures analysis, after adjustm ent for age, body mass index (BMI) and year of study, showed a significant effect of fenretinide on IGF-I levels, which were further lowered after the second year of treatment and only partially recovered after drug discontin uation. Differently from breast cancer patients, the effect of fenretinide was not modified by age. No significant effect was evident on IGFBP-3, IGF- II and the IGF-I+IGF-II/IGFBP-3 molar ratio, expressing the tissue availabi lity of the mitogenic peptides, although IGF-II and the molar ratio were lo wered by treatment by an overall mean of 16% and 15%, respectively. Given t he increasingly recognized importance of circulating IGFs in the pathogenes is of different solid tumors, our findings strengthen the rationale for stu dying fenretinide as a chemopreventive agent. Int, J. Cancer 87:601-605, 20 00. (C) 2000 Wiley-Liss, Inc.