Egner P A, Gange S J, Dolan P M, Groopman J D, Muñoz A, Kensler T W
Department of Environmental Health Sciences, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD 21205, USA.
Carcinogenesis. 1995 Aug;16(8):1769-73. doi: 10.1093/carcin/16.8.1769.
The validation process for biomarkers to be used for monitoring the efficacy of preventive interventions in humans includes assessments of whether levels of the biomarker can be modulated in experimental models. From this perspective, the influence of two intervention protocols with the chemopreventive agent oltipraz on rates of formation and disappearance of aflatoxin-albumin adducts has been evaluated in rats chronically exposed to aflatoxin B1. Male F344 rats were treated daily with 20 micrograms aflatoxin B1, p.o. for 35 days. The first strategy employed a standard, long-term intervention in which basal AIN-76A diet was supplemented with 0.05% oltipraz beginning one week before AFB1 treatment and continuing throughout the period of carcinogen exposure. In this setting, treatment with oltipraz reduced the rate of formation of aflatoxin-albumin adducts such that steady-state levels were lowered by > 50% from control values of 400 pmol aflatoxin adducts/mg albumin. The time-course for reaching respective steady-state levels was unchanged, with or without oltipraz intervention. The second intervention strategy utilized a delayed, transient protocol in which oltipraz was fed for 2 weeks beginning 1 week after AFB1 dosing began and ending 2 weeks before AFB1 dosing was completed. This second strategy, which models clinical interventions in chronically exposed individuals, produced a steady decline in aflatoxin-albumin adduct levels that approached a 50% reduction by the end of the AFB1 exposure period. Development of smooth curve functions allowed for the estimation of the ratio of effects between the non-intervention and intervention groups as well as the simultaneous 90% confidence intervals for the aflatoxin-albumin adduct levels. These analyses indicated that long-term intervention with oltipraz produced a statistically significant reduction in levels of the aflatoxin-albumin biomarker at all times throughout aflatoxin exposure. By contrast, a statistically significant decrease in biomarker levels was not seen in the delayed, transient intervention protocol until the ninth day of the intervention. However, once achieved, significant differences from the control group were maintained for the remainder of the aflatoxin exposure period. These changes in aflatoxin biomarker levels are consistent with the cancer chemopreventive outcomes of these intervention protocols in rats. Collectively, these results support the utility of measuring this biomarker as a means for assessing the efficacy or chemopreventive interventions in individuals at high risk for aflatoxin exposure and development of hepatocellular carcinoma.
用于监测人类预防性干预措施疗效的生物标志物的验证过程包括评估该生物标志物的水平在实验模型中是否可被调节。从这个角度来看，在长期暴露于黄曲霉毒素B1的大鼠中，评估了两种使用化学预防剂奥替普拉的干预方案对黄曲霉毒素 - 白蛋白加合物形成和消失速率的影响。雄性F344大鼠每天经口给予20微克黄曲霉毒素B1，持续35天。第一种策略采用标准的长期干预，即在AFB1处理前一周开始，在整个致癌物暴露期间，在基础AIN - 76A饮食中添加0.05%的奥替普拉。在这种情况下，奥替普拉治疗降低了黄曲霉毒素 - 白蛋白加合物的形成速率，使得稳态水平比400 pmol黄曲霉毒素加合物/毫克白蛋白的对照值降低了>50%。无论有无奥替普拉干预，达到各自稳态水平的时间进程都没有变化。第二种干预策略采用延迟的短暂方案，即在AFB1给药开始1周后开始给予奥替普拉2周，并在AFB1给药完成前2周结束。这种模拟长期暴露个体临床干预的第二种策略使黄曲霉毒素 - 白蛋白加合物水平稳步下降，到AFB1暴露期结束时接近降低50%。平滑曲线函数的开发使得能够估计非干预组和干预组之间的效应比以及黄曲霉毒素 - 白蛋白加合物水平的同时90%置信区间。这些分析表明，在整个黄曲霉毒素暴露期间，奥替普拉的长期干预在所有时间点都使黄曲霉毒素 - 白蛋白生物标志物水平产生了统计学上的显著降低。相比之下，在延迟的短暂干预方案中，直到干预的第九天才观察到生物标志物水平有统计学上的显著下降。然而，一旦实现，在黄曲霉毒素暴露期的剩余时间内与对照组保持显著差异。黄曲霉毒素生物标志物水平的这些变化与这些干预方案在大鼠中的癌症化学预防结果一致。总体而言，这些结果支持测量这种生物标志物作为评估黄曲霉毒素暴露和肝细胞癌发生高风险个体中化学预防干预疗效的一种手段的实用性。
