Szarka C E, Yao K S, Pfeiffer G R, Balshem A M, Litwin S, Frucht H, Goosenberg E B, Engstrom P F, Clapper M L, O'Dwyer P J
Fox Chase Cancer Center, Department of Population Science, Philadelphia, PA 19111, USA.
Cancer Detect Prev. 2001;25(4):352-61.
The dithiolethione oltipraz is being developed as a chemopreventive agent for many malignancies, including colorectal cancer, on the basis of its in vivo protective activity against chemically induced tumors in a variety of animal models. This protection has been associated with an enhanced capacity to detoxify reactive carcinogens and, more recently, with increased DNA repair. In a previous single-dose study, elevated detoxification gene expression was observed in the days after oltipraz dosing. Now, in this clinical study, we evaluated the effects of oltipraz when given over a 3-month period. Fourteen individuals with increased risk for colorectal cancer were randomly assigned to one of two oral doses (125 or 250 mg/m2) of oltipraz twice weekly for 12 weeks. Two of seven subjects at the 250 mg/m2 dosage required dose reductions, owing to significant fatigue. The 125 mg/m2 dose level was well tolerated by all patients. Blood or colon tissue (or both) for evaluation of glutathione, glutathione S-transferase, DT-diaphorase activity, and DT-diaphorase mRNA expression were obtained prior to treatment and at weeks 6, 12, and 16. No significant modulation of phase II detoxification enzymes was seen at either dose studied during this period. Phase II trials evaluating a tolerable regimen of oltipraz (as demonstrated in this study) and other possible mechanisms that may be responsible for the protective activity of oltipraz should be pursued.
二硫杂环戊烯类化合物奥替普拉，基于其在多种动物模型中对化学诱导肿瘤的体内保护活性，正被开发用作包括结直肠癌在内的多种恶性肿瘤的化学预防剂。这种保护作用与增强的活性致癌物解毒能力有关，最近还与DNA修复增加有关。在之前的一项单剂量研究中，在奥替普拉给药后的几天内观察到解毒基因表达升高。现在，在这项临床研究中，我们评估了连续3个月服用奥替普拉的效果。14名结直肠癌风险增加的个体被随机分配到两种口服剂量（125或250 mg/m²）之一，每周两次，持续12周。250 mg/m²剂量组的7名受试者中有2名因严重疲劳需要减少剂量。125 mg/m²剂量水平所有患者均耐受良好。在治疗前以及第6、12和16周采集血液或结肠组织（或两者），以评估谷胱甘肽、谷胱甘肽S-转移酶、DT-黄递酶活性和DT-黄递酶mRNA表达。在此期间，在所研究的两种剂量下均未观察到II期解毒酶有明显调节。应进行II期试验，评估奥替普拉的可耐受方案（如本研究所示）以及可能负责奥替普拉保护活性的其他潜在机制。
