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
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.
Eur J Cancer Prev. 2016 Jul;25(4):312-20. doi: 10.1097/CEJ.0000000000000189.
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-DIM) 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-DIM 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.
十字花科蔬菜生物活性代谢产物3,3'-二吲哚甲烷（DIM）的流行病学、临床前及早期I期研究支持其具有潜在的前列腺癌化学预防能力。我们对诊断为前列腺癌且计划进行根治性前列腺切除术的患者开展了一项关于DIM的多中心、双盲、安慰剂对照试验。共有45例器官局限性前列腺癌患者被随机分为两组，一组接受吸收增强型DIM制剂（BR-DIM），剂量为每日口服两次，每次100或200毫克，共服用21 - 28天；另一组每日口服两次安慰剂。DIM在前列腺组织中的水平是主要终点指标，选定的次要生物标志物终点指标包括DIM的血液水平、总前列腺特异性抗原、睾酮、胰岛素样生长因子-1与胰岛素样生长因子结合蛋白-3的比值以及尿2-羟雌酮/16-羟雌酮比值，这些指标在基线、第15天和手术前进行检测，同时检测雄激素受体、前列腺特异性抗原、Ki67、半胱天冬酶3的组织表达以及细胞色素P450 mRNA表达和基因分型（多态性）。DIM耐受性良好，研究依从性极佳，所有45例患者在1年内较快入组。在28份前列腺组织标本中，仅7份检测到了DIM水平。安慰剂组和400毫克DIM组从基线到手术前尿2-羟雌酮/16-羟雌酮比值的变化存在统计学显著差异，而血浆生物标志物表达的其他变化无统计学意义。在前列腺切除术前给前列腺癌患者服用BR-DIM可检测到血浆水平，但未出现一致或显著的组织蓄积或生物标志物调节。本研究证明了在前列腺切除术前环境中对相对无毒的预防剂进行生物学评估的可行性，且具有快速入组的潜力。
