Karmanos Cancer Institute, Wayne State University Detroit, MI, USA.
Am J Transl Res. 2010 Jul 23;2(4):402-11.
3, 3'-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen which down-regulates the androgen receptor and prostate specific antigen (PSA). We conducted a dose-escalation, phase I study of BioResponse (BR)-DIM with objectives to determine the maximum tolerated dose (MTD), toxicity profile, and phar-macokinetics (PK) of BR-DIM, and to assess its effects on serum PSA and quality of life (QoL).
Cohorts of 3-6 patients received escalating doses of twice daily oral BR-DIM providing DIM at 75 mg, then 150 mg, 225 mg, and 300 mg. Toxicity was evaluated monthly. Serum PSA and QoL were measured at baseline, monthly during treatment, and at end of study.
12 patients with castrate-resistant, non-metastatic, PSA relapse prostate cancer were treated over 4 dose cohorts; 2 patients (at 150 mg and 225 mg, respectively) underwent intra-patient dose escalation, by one dose level. After oral administration of the first dose of BR-DIM, the plasma exposure to DIM appeared dose proportional at doses ranging from 75 to 300 mg, with the mean C(max) and mean AUC(last) increasing from 41.6 to 236.4 ng/ml and from 192.0 to 899.0 ng/ml*h, respectively. Continued relatively stable systemic exposure to DIM was achieved following twice daily oral administration of BR-DIM. Minimal toxicity was observed. Two of the four patients treated at 300 mg had grade 3 asymptomatic hyponatremia (AH) discovered on routine blood work. The other 2 patients at this dose had no AH. Therefore, the maximum tolerated dose (MTD) was deemed to be 300 mgand the recommended phase II dose (RP2D) of BR-DIM was 225 mg twice daily. One patient without AH at 225 mg experienced a 50% PSA decline. One patient with BR-DIM dose of 225 mg had PSA stabilization. The other 10 patients had an initial deceleration of their PSA rise (decrease in slope), but eventually progressed based on continual PSA rise or evidence of metastatic disease. Ten patients completed monthly QoL reports for a mean of 6 months (range: 1-13). QoL measures emotional functioning may have held up somewhat better over time than their physical functioning.
BR-DIM was well tolerated. Increasing systemic exposure to DIM was achieved with the increase of BR-DIM dose. Modest efficacy was demonstrated. Patients' QoL varied over time with length of treatment. Phase II studies are recommended at the dose of 225 mg orally twice daily.
确定最大耐受剂量（MTD）、毒性谱和生物反应（BR）-DIM 的药代动力学（PK），并评估其对血清 PSA 和生活质量（QoL）的影响。
每 3-6 名患者一组接受每日两次口服 BR-DIM 的递增剂量，提供 75mg、150mg、225mg 和 300mg 的 DIM。每月评估毒性。在基线、治疗期间每月和研究结束时测量血清 PSA 和 QoL。
12 名接受去势抵抗、非转移性、PSA 复发前列腺癌治疗的患者接受了 4 个剂量组；2 名患者（分别在 150mg 和 225mg 时）通过一个剂量水平进行了患者内剂量递增。口服 BR-DIM 首剂量后，在 75 至 300mg 剂量范围内，DIM 的血浆暴露量呈剂量比例关系，平均 C(max)和平均 AUC(last)分别从 41.6ng/ml 增加到 236.4ng/ml，从 192.0ng/mlh 增加到 899.0ng/mlh。每日两次口服 BR-DIM 可实现对 DIM 的相对稳定的全身暴露。观察到最小的毒性。4 名接受 300mg 治疗的患者中有 2 名出现无症状性低钠血症（AH），在常规血液检查中发现。另外 2 名接受该剂量的患者没有 AH。因此，最大耐受剂量（MTD）被认为是 300mg，BR-DIM 的推荐 II 期剂量（RP2D）为 225mg，每日两次。1 名在 225mg 时没有 AH 的患者 PSA 下降 50%。1 名接受 225mg BR-DIM 的患者 PSA 稳定。另外 10 名患者的 PSA 上升速度最初减慢（斜率下降），但最终根据 PSA 持续上升或转移性疾病的证据进展。10 名患者完成了平均 6 个月（范围：1-13）的每月 QoL 报告。随着治疗时间的延长，衡量情感功能的 QoL 指标可能保持得更好。
BR-DIM 耐受性良好。随着 BR-DIM 剂量的增加，实现了对 DIM 的系统暴露增加。显示出适度的疗效。患者的 QoL 随治疗时间的变化而变化。建议在口服 225mg 每日两次的剂量下进行 II 期研究。
