Abstract 706: Efficacy evaluation of BR-9001, a SMEDDS formulation of 3,3’-diindolylmethane, as an inhibitor of preneoplastic and neoplastic lesion development in the prostate of Hi-Myc mice

Self-Microemulsifying Drug Delivery Systems (SMEDDS) can greatly increase the bioavailability of agents with limited solubility. Studies were performed to characterize the efficacy of BR-9001, a SMEDDS formulation of 3,3’-diindolylmethane (DIM), in preventing preneoplastic and neoplastic prostate lesion development in Hi-Myc mice. Beginning at age 8 weeks, groups of 105 male Hi-Myc mice received twice daily oral (gavage) administration of BR-9001 (BioResponse LLC, Boulder, CO) at DIM-equivalent doses of 0 (vehicle control), 200, or 400 mg/kg/dose. At ages 4 months, 5.5 months, and 7 months, cohorts of 35 mice/group were euthanized and necropsied; at each time point, tissues were collected from 25 mice/group for pathology; 5 mice/group for analysis of DIM levels in the plasma and prostate; and 5 mice/group for biomarker analysis. Prostate lesion development in pathology cohorts was determined by microscopic evaluation of step sections through the entire accessory sex gland block. Plasma and prostate levels of DIM were quantitated by LC-MS/MS; biomarkers were analyzed by RT-PCR. Administration of BR-9001 produced dose-related levels of DIM in the plasma and prostate at all time points. However, BR-9001 provided at most limited protection against prostate lesion development. Most lesions were identified in the lateral prostate (LP), where statistically significant reductions in incidences of murine prostatic intraepithelial neoplasias (mPIN) were seen in 4-month-old mice receiving the high dose of BR-9001 and in 5.5-month-old and 7-month-old mice receiving the low dose of BR-9001. Reductions in mPIN incidence in groups receiving BR-9001 were due to lower incidences of small mPIN lesions; incidences of large mPIN were significantly increased at 5.5 months in both groups receiving BR-9001. BR-9001 had no statistically significant effect on % occupancy of the LP by mPIN, the incidence of microinvasive mPIN in the LP, or cancer incidence in the LP. In the anterior prostate (AP), incidences of atypical hyperplasia were similar in all groups. However, at all necropsy time points, mice receiving the high dose of BR-9001 demonstrated significant increases in the incidences of moderate to marked AP atypia; these increases were accompanied by decreases in the incidence of mice with slight to moderate AP atypia. None of 22 potential molecular biomarkers were found to be clearly linked to development and progression of prostate lesions in Hi-Myc mice. Despite the presenc