Saturday, June 30, 2007

DIM Clinical Applications and Research

DIM is currently used to treat Recurring Respiratory Papillomatosis caused by the Human Papilloma Virus and is in Phase III clinical trials for Cervical Dysplasia at 2mg/kg of body weight. Cervical Dysplasia is a precancerous condition also caused by the Human Papilloma Virus. Until recently, DIM's biological mode of action for these conditions was not clearly understood, until scientists discovered that DIM is a potent modulator of the innate immune response system, which then placed DIM's anti-viral activity against the Human Papilloma Virus in perspective.

As a result of this discovery, DIM is currently sold as an immune enhancing supplement ( and it is under investigation as a therapeutic for viral and bacterial infections (including HIV, HPV, Hepatitis, Influenza, the Pandemic Flu and antibiotic resistant bacteria), immune deficiency conditions and multiple forms of cancer. DIM's primary immune modulatory mode of action is the stimulation of Interferon-Gamma receptor transcription as well as the production of Interferon-Gamma. DIM has also been shown to synergize with Interferon-Gamma in the potentiation of the MHC-I Complex.

Its multitude of favorable biological activities such as immune modulation, apoptosis and suppression of inflammation (NFkB) are among the reasons why the National Cancer Institute has begun clinical studies of DIM for multiple forms of cancer.

Another significant discovery that has recently been made about DIM that has fueled international interest in this unique phytochemical is its synergy with the number one cancer drug worldwide (Taxol) in the promotion of apoptosis. This discovery has paved the way for the investigation of DIM as an adjuvant therapeutic to Taxol to reduce patient resistance to this important drug. (Taxol is another plant-derived chemical that was discovered in and extracted from the Pacific Yew Tree.)

UC Berkeley faculty members Dr. Leonard Bjeldanes, Professor and former Chairman of the Nutritional Sciences and Toxicology Department, and Dr. Gary Firestone, Director of the NIH Cancer Biology Program and Professor of the Molecular and Cell Biology Department, have focused on DIM research at Berkeley for over two decades and have elucidated many of its principal molecular mechanisms of action.

In addition to elucidating DIM's molecular mechanisms of action, Dr. Bjeldanes and Dr. Firestone conducted a human clinical trial of DIM and demonstrated that it increases the 2-hydroxylation of estrogen metabolites, a study that received a lot of media attention as oncologists believe that this activity helps to reduce the risk of breast and prostate cancer. Abstracts of two papers on this subject are provided below.

Pilot study: effect of 3,3'diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Journal of Nutrition and Cancer. 2004;50(2):161-7. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3200, USA.

Dietary indoles, present in Brassica plants such as cabbage, broccoli, and Brussels sprouts, have been shown to provide potential protection against hormone-dependent cancers. 3,3'-Diindolylmethane (DIM) is under study as one of the main protective indole metabolites. Postmenopausal women aged 50-70 yr from Marin County, California, with a history of early-stage breast cancer, were screened for interest and eligibility in this pilot study on the effect of DIM supplements on urinary hormone metabolites. The treatment group received daily DIM (108 mg DIM/day) supplements for 30 days, and the control group received a placebo capsule daily for 30 days. Urinary metabolite analysis included 2-hydroxyestrone (2-OHE1), 16-alpha hydroxyestrone (16alpha-OHE1), DIM, estrone (El), estradiol(E2), estriol (E3), 6beta-hydroxycortisol (6beta-OHC), and cortisol in the first morning urine sample before intervention and 31 days after intervention. Nineteen women completed the study,for a total of 10 in the treatment group and 9 in the placebo group. DIM-treated subjects, relative to placebo, showed a significant increase in levels of 2-OHE1 (P=0. 020), DIM (P =0. 045), and cortisol (P = 0.039), and an increase of 47% in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). In this pilot study, DIM increased the 2-hydroxylation of estrogen urinary metabolites.

Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40. Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ, Stanulla M, Yang J, Sepkovic DW, Trevisan M, Berrino F. Department of Social and Preventive Medicine, University at Buffalo, State University of New York at Buffalo, Buffalo, NY, USA, Epidemiology Division of the National Cancer Intitute (Istituto Nazionale Tumori), Milan, Italy, Department of Pediatric Hematology and Oncology, Medical School of Hannover, Hannover, Germany.

Experimental and clinical evidence suggests that 16alpha-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35-69 years) were recruited to a prospective study on breast cancer in Italy, the "Hormones and Diet in the Etiology of Breast Cancer" (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at -80 degrees C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25-1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53-3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16alpha-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.


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