Groopman J D, DeMatos P, Egner P A, Love-Hunt A, Kensler T W
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
Carcinogenesis. 1992 Jan;13(1):101-6. doi: 10.1093/carcin/13.1.101.
Hepatocellular carcinoma has one of the poorest 5 year survival rates of any human cancer. Preventive measures offer the best possibility of ameliorating this disease and chemoprotective agents are being developed for this purpose. The dithiolethiones, including oltipraz and the unsubstituted molecule 1,2-dithiole-3-thione, have been shown to be potent inhibitors of aflatoxin-induced hepatic tumorigenesis in rats. However, subsequent evaluation of dithiolethiones or other chemoprotective agents in human clinical trials will require the development of intermediate, non-invasive biomarkers to evaluate the efficacy of these interventions. In this study, levels of molecular dosimetry biomarkers for determining genotoxic damage caused by aflatoxin B1 have been measured in a chronic exposure model with male F344 rats wherein half the animals were fed a diet supplemented with 0.03% 1,2-dithiole-3-thione to lower their risk for tumors and the other half were fed unsupplemented AIN-76A diet and were at high risk for tumor development. Levels of hepatic aflatoxin-DNA adducts, serum aflatoxin-albumin adducts and excreted aflatoxin-N7-guanine adducts in urine were determined following multiple administrations of 250 micrograms aflatoxin B1/kg body wt on days 0-4 and 7-11 to assess the use of the serum and urinary biomarkers as indices of chemoprotective efficacy. In the rats fed 1,2-dithiole-3-thione, the overall diminutions in the levels of hepatic DNA adducts, urinary aflatoxin-N7-guanine and serum aflatoxin-albumin adducts over the 2 week exposure period were 76, 62 and 66% respectively. This parallelism in reductions of levels of biomarkers relative to target organ DNA adduct burden suggests that these biomarkers are predictive short-term, non-invasive measures for assessing the efficacy of chemoprotective interventions in experimental studies and can be applied to human clinical trials directed at populations at high risk for aflatoxin exposure and primary hepatocellular carcinoma.
肝细胞癌是所有人类癌症中5年生存率最低的癌症之一。预防措施为改善这种疾病提供了最佳可能性，为此正在开发化学预防剂。二硫代硫酮，包括奥替普拉和未取代的分子1,2 - 二硫代-3-硫酮，已被证明是大鼠黄曲霉毒素诱导的肝肿瘤发生的有效抑制剂。然而，随后在人类临床试验中对二硫代硫酮或其他化学预防剂的评估将需要开发中间的、非侵入性生物标志物来评估这些干预措施的疗效。在本研究中，在雄性F344大鼠的慢性暴露模型中测量了用于确定黄曲霉毒素B1引起的基因毒性损伤的分子剂量生物标志物水平，其中一半动物喂食补充有0.03% 1,2 - 二硫代-3-硫酮的饮食以降低其肿瘤风险，另一半喂食未补充的AIN - 76A饮食且处于高肿瘤发生风险中。在第0 - 4天和第7 - 11天多次给予250微克黄曲霉毒素B1/kg体重后，测定肝黄曲霉毒素-DNA加合物、血清黄曲霉毒素-白蛋白加合物和尿中排泄的黄曲霉毒素-N7-鸟嘌呤加合物水平，以评估血清和尿生物标志物作为化学预防疗效指标的用途。在喂食1,2 - 二硫代-3-硫酮的大鼠中，在2周暴露期内肝DNA加合物、尿黄曲霉毒素-N7-鸟嘌呤和血清黄曲霉毒素-白蛋白加合物水平的总体降低分别为76%、62%和66%。相对于靶器官DNA加合物负荷的生物标志物水平降低的这种平行性表明，这些生物标志物是用于评估实验研究中化学预防干预疗效的预测性短期、非侵入性措施，并且可应用于针对黄曲霉毒素暴露和原发性肝细胞癌高风险人群的人类临床试验。
