The effects of BR-DIM (BioResponse 3, 3’-Diindolylmethane) administered pre-prostatectomy on the androgen receptor (AR).

Abstract

1560 Background: Consumption of cruciferous vegetables is associated with decreased risk of prostate cancer (PCa). 3,3’-diindolylmethane (DIM), an in vivo active compound formed after consumption of cruciferous vegetables, down-regulates the AR, and causes its nuclear exclusion which results in in vitro growth arrest and apoptosis of PCa cells. We conducted a biomarker trial evaluating BR-DIM in pre-prostatectomy patients with the primary objective of measuring DIM levels in prostate tissue and in plasma. Methods: Patients with organ-confined PCa who were candidates for surgery were treated with BR-DIM at a dose of 225 mg orally twice daily for a minimum of 14 days. Patients did not receive any androgen deprivation therapy. Patients received their last dose of BR-DIM the day before surgery. Blood samples for DIM levels were collected pre-treatment and just prior to surgery. DIM concentration was measured in the plasma and in prostate tissue specimens using a validated high-performance liquid chromatographic method with tandem mass spectrometric detection. AR was evaluated by immunohistochemistry (IHC). Results: 36 patients were treated at 2 institutions. The 26 evaluable patients had median age of 60 years (range 41 - 76), 14 were Caucasian, and 10 were African American. Reasons for inevaluability included change in surgery date (n=4), inadequate BR-DIM treatment (2), withdrawal from study (2), canceled surgery (1), and other (1). Toxicity was minimal; only two patients with grade 3 headache. Post dosing, DIM was found at a mean trough level of 10.2 ng/ml (range, 0.5 to 24.7) and 12.3 ng/gm of tissue (range, 0.0 to 26.8) in plasma and in prostate tissue, respectively. PSA levels had a slightly downward trend after BR-DIM treatment. In 18 of 20 evaluable PCa specimens, IHC showed nuclear exclusion of AR. Conclusions: BR-DIM was well tolerated, and DIM was detected in both plasma and prostate tissues at ~12 h post dosing. Nuclear exclusion of AR was found in 90% of PCa specimens post BR-DIM dosing, suggesting in vivo inactivation of AR activity. PSA levels were slightly reduced overall. Accrual is ongoing and nearly complete. Additional studies with BR-DIM in PCa are warranted.