Placebo-Controlled Trial of Indole-3-Carbinol in the Treatment of CIN
ABSTRACT Most precancerous lesions of the cervix are treated with surgery or ablative therapy. Chemoprevention, using natural and synthetic compounds, may intervene in the early precancerous stages of carcinogenesis and prevent the development of invasive disease. Our trial used indole-3-carbinol (I-3-C) administered orally to treat women with CIN as a therapeutic for cervical CIN.
Thirty patients with biopsy proven CIN II-III were randomized to receive placebo or 200, or 400 mg/day I-3-C administered orally for 12 weeks. If persistent CIN was diagnosed by cervical biopsy at the end of the trial, loop electrocautery excision procedure of the transformation zone was performed. HPV status was assessed in all patients.
None (0 of 10) of the patients in the placebo group had complete regression of CIN. In contrast 4 of 8 patients in the 200 mg/day arm and 4 of 9 patients in the 400 mg/day arm had complete regression based on their 12-week biopsy. This protective effect of I-3-C is shown by a relative risk (RR) of 0.50 ((95% CI, 0. 25 to 0.99) P = 0.023) for the 200 mg/day group and a RR of 0.55 ((95% CI, 0.31 to 0.99) P = 0.032) for the 400 mg/day group. HPV was detected in 7 of 10 placebo patients, in 7 of 8 in the 200 mg/day group, and in 8 of 9 in the 400 mg/day group.
There was a statistically significant regression of CIN in patients treated with I-3-C orally compared with placebo. The 2/16 alpha-hydroxyestrone ratio changed in a dose-dependent fashion.
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ABSTRACT: Cervical cancer is a public health issue in developing countries. Although the Pap smear and colposcopy remain the major strategies for detection, most cases are diagnosed in the late stages. Therefore, a major concern has been to develop early diagnostic approaches and more effective treatments. Molecular pathways that participate in cervical malignant transformation have emerged as promising directed therapeutic targets. In this review, we explore some of the major pathways implicated in cervical cancer development, including RAF/MEK/ERK, phosphatidylinositol-3 kinase (PI3K/AKT), Wnt/b-catenin, apoptosis and coupled membrane receptor signaling. We focus on the role of these pathways in cervical carcinogenesis, their alterations and the consequences of these abnormalities. In addition, the most recent preclinical and clinical data on the rationally designed target-based agents that are currently being tested against elements of these pathways are reviewed. Copyright © 2014 IMSS. Published by Elsevier Inc. All rights reserved.Archives of Medical Research 11/2014; 45(7). DOI:10.1016/j.arcmed.2014.10.008 · 2.41 Impact Factor
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ABSTRACT: Introduction: Current treatments for high-grade cervical intraepithelial neoplasia (CIN2/3) are mainly excisional procedures, which are associated with significant side effects and pose risks for future pregnancies. An effective and safe therapy is needed to reduce the requirement for surgical interventions in women of reproductive age.Areas covered: This review looks at the pharmacokinetic and clinical data for topical hexaminolevulinate (HAL) photodynamic therapy (PDT), which is currently entering late phase clinical trials for high-grade CIN. The authors include published studies in patients and volunteers but laboratory and animal studies have been excluded as have studies on other porphyrins such as Photofrin, 5-aminolevulinic acid, methyl aminolevulinate and studies reporting other clinical applications for HAL.Expert opinion: Topical HAL PDT has potential as a non-surgical tissue-preserving treatment for CIN and persistent oncogenic human papilloma virus infections. HAL PDT selectively treats the entire epithelial sheet, without the tissue destruction seen in excisional procedures. The authors believe that this treatment could replace surgery in a large proportion of patients. It would be of particular value to the high percentage of women who are interested in future child-bearing. If the treatment is approved, it is very likely that physicians will want to use this treatment, as many patients will be keen to consider a non-surgical option.Expert Opinion on Investigational Drugs 12/2014; 24(2). DOI:10.1517/13543784.2015.990150 · 4.74 Impact Factor
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ABSTRACT: Strong evidence exists to suggest that increased consumption of glucosinolates from Brassica vegetables is associated with reduced risk of cancer induction and development. Development of elite germplasm of these vegetables with enhanced levels of glucosinolates will putatively enhance health promotion among the consuming public. To evaluate levels of glucosinolate phenotypic variation in Chinese cabbage tissue and partition the total phenotypic variation into component sources (genotype, environment, and genotype-by-environment interaction), a set of 23 Brassica rapa L. var. pekinensis genotypes were grown in two different environments (field plots and greenhouse ground beds). Gluconasturtiin and glucobrassicin were found to account for %80% of total head glucosinolate content. Significant differences were found in glucosinolate concentrations between the lowest and highest genotypes for glucobrassicin (6-fold) and for gluconasturtiin (2.5-fold). Analysis of variance showed that for the three major glucosinolates (gluconasturtiin, glucobrassicin, and progoitrin), the genotypic effects described most of the phenotypic variation (62% averaged over the three compounds). The next most important factor was genotype · environment interaction (29%), whereas variation affiliated with the environment was found to be relatively minor (8%). These results suggest that genetic manipulation and selection can be conducted to increase glucosinolate content and the putative health promotion associated with consumption of Chinese cabbage. Epidemiological studies have suggested that an inverse relationship exists between dietary intake of phytochemicals called glucosinolates in Brassica vegetables and induction of cancer (Verhoeven et al., 1996). Glucosinolates are a group of sulfur-containing glucosides naturally occurring in cruciferous vegetables that are hydrolyzed by the endogenous enzyme myrosinase into isothiocyanates, thiocyanates, and nitriles (Fenwick et al., 1983). The primary forms of these phytochemicals include the ali-phatic, indolyl, and aromatic glucosinolates derived from the amino acid precursors methionine, tryptophan, and phenylalanine respectively. Chinese cabbage (Brassica rapa L. var. pekinensis) is a relatively rich source of these chemicals, particularly gluconasturtiin (aromatic glucosinolate), glucobrassicin (indolyl glucosinolate), and progoitrin (aliphatic glucosinolate) (Daxen-bichler et al., 1979). Gluconasturtiin and glucobrassicin are precursors to phenethlyi-sothiocyanate (PEITC) and indole-3-carbanol (I3C), strong inhibitors of carcinogenesis in mammalian systems (Bell et al., 2000; Hecht, 2000; Wong et al., 1997). In contrast hydro-lyzed products of progoitrin have demon-strated goitrogenic activity in animals, but in most cases this appears to be limited to situations of iodine deficiency (Jongen, 1996). Based on epidemiological, cell culture, and animal model studies, PEITC and I3C are currently undergoing clinical trials, and ap-pear to slow or prevent several forms of cancer successfully (Bell et al., 2000; Wong et al., 1997). I3C, derived from glucobrassi-cin in cruciferous vegetables, has been shown to the lower incidence of hormone-dependent cancers by altering estrogen metabolism (Fowke et al., 2000; Keck and Finley, 2004). In the stomach, I3C is transformed into various bioactive compounds that can influence estrogen metabolism and promote hydroxylated metabolites at the C-2 position of the estrogen molecule and prevent hydrox-ylation at the C-16 position. Several inves-tigations suggest that women who metabolize a large proportion of their estrogens in the form of 2-OH estrone as opposed to theHortScience: a publication of the American Society for Horticultural Science 01/2006; 41(6):1382-1385. · 0.86 Impact Factor