Kensler T W, He X, Otieno M, Egner P A, Jacobson L P, Chen B, Wang J S, Zhu Y R, Zhang B C, Wang J B, Wu Y, Zhang Q N, Qian G S, Kuang S Y, Fang X, Li Y F, Yu L Y, Prochaska H J, Davidson N E, Gordon G B, Gorman M B, Zarba A, Enger C, Muñoz A, Helzlsouer K J
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA.
Cancer Epidemiol Biomarkers Prev. 1998 Feb;7(2):127-34.
In 1995, 234 adults from Qidong, People's Republic of China, were enrolled and followed in a Phase IIa 4-methyl-5-(N-2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) chemoprevention trial. Residents of this area are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods. The intervention was a randomized, placebo-controlled, double-blind study. Elements of the study design and clinical outcomes have been recently published (Jacobson et al, Cancer Epidemiol. Biomark. Prev., 6: 257-265, 1997). The primary objective was to conduct a preliminary assessment of the ability of oltipraz to modulate levels of a validated biomarker of aflatoxin exposure and of the risk of hepatocellular carcinoma by determining levels of aflatoxin-albumin adducts in sera. Healthy eligible individuals were randomized into three arms to receive p.o. 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo for 8 weeks. There were no consistent changes in biomarker levels in the placebo arm over the 16-week observation period, nor was any apparent effect observed in the arm receiving 125 mg of oltipraz each day. However, individuals receiving 500 mg of oltipraz once a week for 8 weeks showed a triphasic response to oltipraz. No effect was observed during the 1st month of the intervention, whereas a significant (P = 0.001) diminution in adduct levels was observed during the 2nd month of active intervention and during the lst month of follow-up. A partial rebound in adduct levels toward baseline values was observed during the 2nd month postintervention. Linear regression models up to week 13 confirmed a significant (P = 0.008) weekly decline of biomarker levels in the group receiving 500 mg of oltipraz once a week. However, despite these effects relative to baseline values within the 500-mg weekly arm, there were no statistically significant differences in biomarker trajectories between treatment arms. The genotype for glutathione S-transferase M1, an oltipraz-inducible isoform involved in the detoxification of aflatoxin B1, did not appear to affect either baseline levels or rates of decline in the biomarker. A follow-up Phase IIb trial with a longer intervention period will be necessary to determine the full extent to which aflatoxin biomarker burden can be reduced and whether diminution of biomarkers can be sustained over the long term.
1995年，来自中华人民共和国启东的234名成年人参加了一项IIa期4-甲基-5-（N-2-吡嗪基）-1,2-二硫杂环戊烯-3-硫酮（oltipraz）化学预防试验并接受随访。该地区居民患肝细胞癌的风险很高，部分原因是食用了受黄曲霉毒素污染的食物。该干预措施是一项随机、安慰剂对照、双盲研究。研究设计要素和临床结果最近已发表（Jacobson等人，《癌症流行病学、生物标志物与预防》，6：257-265，1997年）。主要目标是通过测定血清中黄曲霉毒素-白蛋白加合物的水平，对oltipraz调节黄曲霉毒素暴露有效生物标志物水平以及肝细胞癌风险的能力进行初步评估。符合条件的健康个体被随机分为三组，分别口服125毫克oltipraz每日一次、500毫克oltipraz每周一次或安慰剂，为期8周。在16周的观察期内，安慰剂组的生物标志物水平没有持续变化，每天接受125毫克oltipraz的组也未观察到明显效果。然而，每周一次接受500毫克oltipraz治疗8周的个体对oltipraz表现出三相反应。在干预的第1个月未观察到效果，而在积极干预的第2个月和随访的第1个月观察到加合物水平显著降低（P = 0.001）。干预后第2个月观察到加合物水平部分反弹至基线值。到第13周的线性回归模型证实，每周一次接受500毫克oltipraz的组中生物标志物水平每周显著下降（P = 0.008）。然而，尽管相对于每周500毫克组内的基线值有这些影响，但各治疗组之间生物标志物轨迹没有统计学上的显著差异。谷胱甘肽S-转移酶M1的基因型，一种参与黄曲霉毒素B1解毒的oltipraz诱导型同工酶，似乎既不影响生物标志物的基线水平，也不影响其下降速率。有必要进行一项干预期更长的后续IIb期试验，以确定黄曲霉毒素生物标志物负担能够降低的全部程度，以及生物标志物的降低能否长期维持。
