Dose‐ranging study of Indole‐3‐Carbinol for breast cancer prevention

Abstract

Sixty women at increased risk for breast cancer were enrolled in a placebo-controlled, double-blind dose-ranging chemoprevention study of indole-3-carbinol (I3C). Fifty-seven of these women with a mean age of 47 years (range 22-74) completed the study. Each woman took a placebo capsule or an I3C capsule daily for a total of 4 weeks; none of the women experienced any significant toxicity effects. The urinary estrogen metabolite ratio of 2hydroxyestrone to 16␣-hydroxyestrone, as determined by an ELISA assay, served as the surrogate endpoint biomarker (SEB). Perturbation in the levels of SEB from baseline was comparable among women in the control (C) group and the 50, 100, and 200 mg low-dose (LD) group. Similarly, it was comparable among women in the 300 and 400 mg high-dose (HD) group. Regression analysis showed that peak relative change of SEB for women in the HD group was significantly greater than that for women in the C and LD groups by an amount that was inversely related to baseline ratio; the difference at the median baseline ratio was 0.48 with 95 % confidence interval (0.30, 0.67). No other factors, such as age and menopausal status, were found to be significant in the regression analysis. The results in this study suggest that I3C at a minimum effective dose schedule of 300 mg per day is a promising chemopreventive agent for breast cancer prevention. A larger study to validate these results and to identify an optimal effective dose schedule of I3C for long-term breast cancer chemoprevention will be necessary.

Predicting the physiological relevance of in vitro cancer preventive activities of phytochemicals

“…A dose-dependent effect (placebo, 200 and 400 mg/d for 3 months) was observed in the treatment of cervical intraepithelial neoplasia [7] , and 200 or 400 mg/d were similarly effective against vulval intraepithelial neoplasia [14] . In dose-escalation studies for breast cancer prevention, 300 mg/d (minimum) increased the urinary estrogen metabolite ratio of 2-hydroxyestrone to 16 alpha-hydroxyestrone; 800 mg/d did not provide additional benefits over 400 mg/d in adult women [15,16] . Elevated cytochrome P450 activity was responsible for an increase in 2-hydroxylation of estrogen, increasing the ratio of 2-OH:16-OH estrone [16] , which is regarded as favorable for the prevention of breast cancer and human papilloma virus (HPV)-related neoplasias [7][8][9][10][11][12][13][14] .…”

Multifunctional Aspects of the Action of Indole‐3‐Carbinol as an Antitumor Agent

“…27 A similar six-week study, comparing 0, 50, 100, 200, 300, and 400 mg/day showed that no response was observed at the lower doses, although the responses to 300 and 400 mg were comparable. 28 Cell-culture studies showed that I3C can normalize a pattern of estrogen metabolism in cells treated with DMBA. A similar improvement in the metabolic pattern was also induced by the addition of tamoxifen or HPR to cells treated with DMBA.…”

A Review of the Clinical Efficacy and Safety of Cruciferous Vegetable Phytochemicals

“…I3C supplementation has been investigated in 13 published human studies (Table 1) during the past 15 years, totaling 333 study subjects (an estimated 293 subjects on I3C). [25][26][27][28][29][30][31][32][33][34][35][36][37] Since 1991, I3C has been studied for its use in a number of conditions, including patients with human papillomavirus-induced diseases such as cervical cancer 26 and respiratory papillomatosis, [29][30][31] as well as in those subjects with increased risk for breast cancer, 25,36 vulvar intraepithelial neoplasia, 27 and systemic lupus erythematosus. 32 Favorable shifts in estrogen metabolism were observed in studies using these metabolites as clinical end points.…”

“…In these studies, 30% to 100% of subjects experienced remission or regression of their symptoms. Two studies explored the use of oral I3C in women with increased risk factors for breast cancer 25,36 : approximately 67 women were studied for 4 weeks to 3 months with an oral I3C dose of 50 to 400 mg. Similar to the studies on human papillomavirus-induced diseases, the results were positive, with a beneficial shift in the ratio of estrogen metabolites.…”

“…28,31,34,35 In 3 out of 13 (23%) studies, either no adverse effects were noted or I3C was well tolerated. 26,29,37 Adverse reactions were reported in 6 of the 13 studies (46%), including: skin rash in one subject with systemic lupus erythematosus 32 ; small increases in the liver enzyme SGPT in two female subjects with increased risk for breast cancer 25 ; a slight increase in gastrointestinal motility and a decrease in complaints of constipation in a few female subjects (unspecified number in article, but counted as two subjects in the percentage tally of adverse reactions) 36 ; "mild bowel upset" in a patient with vulvar intraepithelial neoplasia 27 ; disequilibrium in three subjects with respiratory papillomatosis due to deliberate or accidental increased dosages of I3C 30 ; and an episode of bronchospasm in a woman with a previous history of asthma (subject denied at time of enrollment). 33 Therefore, of the total number of subjects in all studies on some dose of I3C (N ϭ 293), about 10 (3%) experienced some degree of a reaction that was most likely due to I3C supplementation within a period of days to years, as reported by the study authors.…”