Implication of insulin-like growth factor (IGF)/IGF binding protein-3 and alpha-tocopherol in the chemopreventive activity of 9-cis retinoic acid in lung cancer

Abstract

1005 Background: High level of IGF-I is associated with increased susceptibility for several types of cancer, whereas high levels of IGFBP-3 and vitamin E tend to attenuate the risk. This study was designed to investigate whether 9-cis-retinoic acid (9cRA) treatment affects the serum IGF-I/IGFBP-3 and alpha-tocopherol (AT), the most active form of vitamin E. Experimental Design: Individuals (n = 226) who had smoked at least 20 pack-year (PY) and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9cRA (100 mg) or placebo arm. During the clinical trial, participants were informed to visit every month and blood samples were taken. After treatment, participants were followed up for another 3 months. Serum levels of IGF-I, IGFBP-3, and AT of participants, who were enrolled in 9cRA (n=49) and placebo (n=55), were measured by the use of HPLC. All statistical tests were two-sided. Results: In 9cRA group, the levels of IGF-I and IGF-I:IGFBP-3 molar ratio were significantly lower, whereas, the levels of IGFBP-3 were significantly higher compared with placebo treated group (P=0.03, <0.01, and 0.03, respectively; Wilcoxon test). The level of IGF-I, IGFBP-3, and its molar ratio in this study population were not affected by the PY and the duration from the smoking cessation to the study. There was no significant difference in the baseline serum AT level between 9cRA and the placebo group. However, the serum level of AT was significantly increased during treatment with 9cRA. It peaked within 1 month and maintained the peak level during 9cRA treatment. Thus the serum level of AT was significantly increased in the 9cRA group compared with the placebo group (r=0.45; p<0.01). There was significant correlation between baseline serum concentration of IGFBP-3 and AT (Pearson's correlation (r)=0.23, p<0.01) and the level of these components was proportionally increased with 9cRA treatment (r=0.45; P<0.01). Conclusions: 9cRA modulated IGF axis and increased serum level of AT in former smokers. These findings suggest that 9cRA has a potential chemopreventive activity in former smokers. No significant financial relationships to disclose.