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Phase Ib placebo-controlled, tissue biomarker trial of diindolylmethane (BR-DIMNG) in patients with prostate cancer who are undergoing prostatectomy

Gee, Jason R.; Saltzstein, Daniel R.; Messing, Edward; Kim, KyungMann; Kolesar, Jill; Huang, Wei; Havighurst, Thomas C.; Harris, Linda; Wollmer, Barbara W.; Jarrard, David; House, Margaret; Parnes, Howard; Bailey, Howard H.

European Journal of Cancer Prevention: July 2016 - Volume 25 - Issue 4 - p 312–320
doi: 10.1097/CEJ.0000000000000189
Research Papers: Prostate Cancer

Epidemiologic, preclinical, and early phase I studies of the cruciferous vegetable bioactive metabolite, 3,3′-diindolylmethane (DIM), support its potential prostate cancer chemopreventive ability. We performed a multicenter, double-blind, placebo-controlled trial of DIM in patients diagnosed with prostate cancer and scheduled for radical prostatectomy. A total of 45 patients with organ-confined prostate cancer were randomized to 21–28 days of an absorption-enhanced formulation of DIM (BR-DIMNG) at doses of 100 or 200 mg per os twice daily or to placebo twice daily. Prostate tissue levels of DIM were the primary endpoint, with selected secondary biomarker endpoints including blood levels of DIM, total prostate-specific antigen, testosterone, and the insulin-like growth factor-1: insulin-like growth factor binding protein-3 ratio and the urinary 2-hydroxyestrone/16-hydroxyestrone ratio, obtained at baseline, at day 15, and before surgery, as well as tissue expression of androgen receptor, prostate-specific antigen, Ki67, caspase 3 with cytochrome p450 mRNA expression and genotyping (polymorphisms). DIM was well tolerated with excellent study compliance and relatively rapid accrual of all 45 patients within 1 year. DIM levels were detected in only seven of 28 prostate tissue specimens. There was a statistically significant difference in the change in the urinary 2-hydroxyestrone/16-hydroxyestrone ratio from baseline until before surgery between the placebo and 400 mg DIM groups, with otherwise statistically nonsignificant changes in plasma biomarker expression. The administration of BR-DIMNG to prostate cancer patients before prostatectomy yields detectable plasma levels but without consistent or significant tissue accumulation or biomarker modulation. This study demonstrates the feasibility of biologic evaluation of relatively nontoxic preventive agents in the preprostatectomy setting with the potential for rapid accrual.

aUniversity of Wisconsin Carbone Cancer Center, Madison, Wisconsin

bUrology San Antonio Research, San Antonio, Texas

cUniversity of Rochester Medical Center, Rochester, New York

dDivision of Cancer Prevention, National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA

Correspondence to Jason R. Gee, MD, Institute of Urology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA 01805, USA Tel: +1 781 744 5481; fax: +1 781 744 5429; e-mail: jason.r.gee@lahey.org

Received January 23, 2015

Accepted July 16, 2015

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