| Clinical
Studies with absorption-enhanced DIM:
Effect of 3,3’-diindolylmethane (DIM) supplements on urinary estrogen
metabolites in postmenopausal women with breast cancer.
Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, and Bjeldanes LF
Dietary indoles, present in Brassica plants such as cabbage, broccoli,
and Brussels sprouts have been shown to be protective against hormone
dependent cancers. 3,3’-diindolylmethane (DIM) is under study as
one of the main protective indole metabolites. Postmenopausal women ages
50-70 from Marin County, California, with a history of early stage breast
cancer, were screened for interest and eligibility in this study on the
effect of absorbable DIM (BioResponse-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-OHE)), 16-alpha hydroxyestrone (16a-OHE1), DIM, estrone (E1), estradiol
(E2), estriol (E3), 6b-hydroxycortisol (6b-OHC), and cortisol in the first
morning urine sample before intervention and 31 days after intervention.
Nineteen women completed the study, making a total of ten in the treatment
group and nine 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 a nonsignificant increase of
47% in the 2-OHE1/16a-OHE1 ratio from 1.46 to 2.14 (p=0.059). These findings
could be associated with a lower risk status for breast cancer.
Proc. Am. Assoc. Cancer Res. 2002 Apr; 43, 3198
Absorption-enhanced 3,3’-Diindolylmethane: Human Use in HPV-related,
Benign and Pre-cancerous Conditions.
Zeligs, M.A., Sepkovic, D.W., Manrique, C., Macsalka, M., Williams, D.E.,and
Bradlow, H.L
3,3'-Diindolylmethane is a dietary indole from cruciferous vegetables
that has demonstrated pre-clinical therapeutic efficacy in models of DMBA-induced
mammary cancer, transplanted human breast cancer, and in models of human
papilloma virus (HPV) related disease. Animal and human use of crystalline
diindolylmethane has revealed the need for absorption-enhancing technology
to allow adequate gastro-intestinal uptake. BioResponse-DIMTM, a patented
formulation of diindolylmethane categorized and sold as a dietary supplement,
utilizes solubility-enhancing micro-encapsulation technology to allow
absorption of effective amounts of diindolylmethane. Human use of this
formulation promotes a dose-responsive upward effect on the urinary ratio
of 2-OH/16a-OH estrone metabolites, demonstrated by ELISA testing of urine
before-and-after use. In previous prospective studies, a greater urinary
2-OH/16a-OH estrone ratio has been associated with a lowered risk of future
breast cancer. We are able to monitor compliance by measurement of urinary
diindolylmethane using a gas chromatography-mass spectrometry method.
Human use of the BioResponse-DIM absorption-enhanced formulation at higher
doses has demonstrated treatment-related resolution of moderate and severe
cervical dysplasia in preliminary open-label testing. A still higher diindolylmethane
dose, about 10 times above that possible from dietary exposure to diindolylmethane
from vegetable sources, has resulted in the control of laryngeal papillomas
and resolution of cutaneous and plantar warts in preliminary human testing.
The clearing of HPV-related lesions is consistent with diindolylmethane’s
previously described, apoptosis-promoting and chemopreventive activity.
Proc. Am. Assoc. Cancer Res. 2003, Apr; 44.
In vivo, uterine-protective activity of absorption-enhanced diindolylmethane:
animal and preliminary human use in combination with Tamoxifen.
Zeligs MA, Fulfs JC, Peterson R, Wilson SM, McIntyre L, Sepkovic
DW, Bradlow HL.
Absorbable Diindolylmethane (BioResponse-DIM® [BR-DIM]) is a patented,
orally active formulation of 3,3'-diindolylmethane (DIM), available as
a dietary supplement. DIM is found in cruciferous vegetables, but also
under investigation for its chemopreventive and pro-apoptotic activities.
Based on DIM's known growth-inhibition of endometrial(1) and cervical
cancer cell lines(2), oral BR-DIM was tested in vivo in a model of estrogen-driven
uterine growth(3) and during monitored use in humans.
Groups of immature female rats were implanted with placebo or androstenedione
pellets and fed either control, or BR-DIM (250 mg/kg/day [62.5 mg/kg/day
DIM]) containing diets. Androstenedione served as a source of aromatase-derived
estrogen. When sacrificed after 72 hrs, the BR-DIM group revealed significantly
lower uterine/body weight indexes (p=0.04) compared to control rats. Thus,
BR-DIM reduced estrogen-related uterine growth in rats.
In monitored human use, BR-DIM, at the label-recommended dose of 300 mg/day
(providing 75 mg/day of DIM), was taken as a dietary supplement by a 41
year old with treated, Stage I breast cancer on Tamoxifen (20 mg/day).
Dysfunctional uterine bleeding and Tamoxifen-related endometrial hyperplasia
were present before BR-DIM use, as confirmed by transvaginal ultrasound
and endometrial biopsy. Following 1 month of BR-DIM use, resolution of
bleeding was noted. Normalization of endometrial contour and thickness
were documented during 3 months of BR-DIM use, and lasting 1 month following
cessation of its use (from 16.0 mm before, to 6.6 mm during, and 5.0 mm
after DIM). 2 months after discontinuing BR-DIM, endometrial thickness
had returned to the pre-treatment level (17.2 mm).
In testing urinary estrone metabolites in women with treated breast cancer,
estrogen 2-hydroxylation was shown to not be influenced by Tamoxifen alone.
During combined Tamoxifen use with BR-DIM, a shift to greater estrogen
2-hydroxylation and less 16-hydroxylation was demonstrated. Therefore,
Tamoxifen did not inhibit promotion of estrogen 2-hydroxylation by BR-DIM.
Women with treated breast cancer responded to BR-DIM with the same increased
2-hydroxylation of estrogen as previously demonstrated in healthy women(4).
Supported by these observations, BR-DIM deserves further evaluation as
a potential uterine protective agent during combined use with Tamoxifen(5)
and during estrogen exposure from HRT(6).
Reference
1. Chen DZ, Qi M, Auborn KJ, Carter TH. Indole-3-carbinol and diindolylmethane
induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic
preneoplastic cervical epithelium. J Nutr. 2001 Dec;131(12):3294-302.
2. Leong H, Firestone GL, Bjeldanes LF. Cytostatic effects of 3,3'-diindolylmethane
in human endometrial cancer cells result from an estrogen receptor-mediated
increase in transforming growth factor-alpha expression.Carcinogenesis.
2001 Nov;22(11):1809-17.)
3. Katzenellenbogen BS, Ferguson ER, Lan NC. Fundamental differences in
the action of estrogens and antiestrogens on the uterus: comparison between
compounds with similar duration of action. Endocrinology. 1977 May;100(5):1252-9.
4. Zeligs, M.A., Sepkovic, D.W., Manrique, C., Macsalka, M., Williams,
D.E.,and Bradlow, H.L. Absorption-enhanced 3,3’-Diindolylmethane:
Human Use in HPV-related, Benign and Pre-cancerous Conditions. Proc. Am.
Assoc. Cancer Res. 2002 Apr; 43, 3198 (Abstract).
5. Kennedy MM, Baigrie CF, Manek S. Tamoxifen and the endometrium: review
of 102 cases and comparison with HRT-related and non-HRT-related endometrial
pathology. Int J Gynecol Pathol. 1999 Apr;18(2):130-7.
6. Gull B, Karlsson B, Milsom I, Granberg S. Factors associated with endometrial
thickness and uterine size in a random sample of postmenopausal women.
Am J Obstet Gynecol. 2001 Aug;185(2):386-91.
7. Crowell JA, Page JD, Zeligs MA, Guyton KZ. Drug Metabolism Enzyme Induction
by Indole-3-Carbinol and Diindolylmethane in Rats, NIH Meeting Abstract,
Amsterdam, September, 2002.
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