文章：

在癌症预防药物开发中评估上皮内瘤变和药物安全性

Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development

原文发布日期：2007-07-01

DOI: 10.1038/nrc2154

类型: Review Article

开放获取: 否

要点：

1. Focusing development efforts for cancer-preventive drugs on precancerous lesions (that is,intraepithelial neoplasia (IEN)) can reduce costs and accelerate the emergence of new cancer-preventive drugs.
2. IEN addresses both risk and clinical endpoints, as it is part of the process of neoplastic progression and not just a biomarker of it.
3. Examples of IEN conferring high risk for progression are colorectal adenomas, breast ductal carcinoma in situ (DCIS), oral dysplasia, high-grade prostatic intraepithelial neoplasia (PIN), Barrett oesophagus and dysplastic nevi. Risk of progression is best estimated by combining IEN with other risk markers/factors.
4. Examples of cancer-prevention clinical endpoints that involve IEN include treatment and prevention of colorectal adenomas, treatment of oral dysplasia, prevention of DCIS and treatment of Barrett oesophagus. In addition to cancer prevention, clinical benefits include reduced morbidity, reduced cost and increased availability of treatment.
5. Several drugs have shown promising efficacy in preventing cancers and in preventing and treating IEN (for example,tamoxifen, raloxifene, celecoxib, finasteride, toremifene, tea polyphenols and statins), but some have also encountered problems that provide lessons that can be applied in future strategies to bring cancer-preventive drugs to market.
6. Demonstrating long-term drug safety is the toughest challenge. Because target populations for cancer-prevention drugs are asymptomatic, and might take the drugs for many years, little toxicity can be tolerated. Methods must be developed to detect and evaluate significant toxicities that occur rarely, and any toxicity that occurs across multiple trials. This might be improved by rigorous post-marketing surveillance.

要点翻译：

1. 将癌症预防药物的研发重点集中于癌前病变（即上皮内瘤变IEN）可降低研发成本并加速新型预防药物的问世。
2. 上皮内瘤变既是风险指标也是临床终点，因为它不仅是肿瘤进展的生物标志物，更是肿瘤进展过程的重要组成部分。
3. 具有高进展风险的上皮内瘤变实例包括：结直肠腺瘤、乳腺导管原位癌、口腔黏膜异常增生、高级别前列腺上皮内瘤变、巴雷特食管及发育不良性痣。结合其他风险标志物/因素可更准确评估进展风险。
4. 涉及上皮内瘤变的癌症预防临床终点案例包括：结直肠腺瘤的治疗与预防、口腔异常增生的治疗、导管原位癌的预防以及巴雷特食管的治疗。除癌症预防外，其临床获益还包括发病率降低、医疗成本减少及治疗可及性提升。
5. 数种药物在预防癌症及防治上皮内瘤变方面已展现出良好疗效（如他莫昔芬、雷洛昔芬、塞来昔布、非那雄胺、托瑞米芬、茶多酚及他汀类药物），但部分药物暴露的问题也为未来抗癌预防药物的上市策略提供了重要借鉴。
6. 证明长期用药安全性是最大挑战。由于癌症预防药物的目标人群无症状且可能长期服药，几乎不能耐受任何毒性。必须建立能有效识别和评估罕见严重毒性反应及跨试验重复出现毒性的方法，加强上市后监管或可改善这一现状。

英文摘要：

Despite significant interest from the research community and the population in general, drug approvals for cancer prevention and/or cancer risk reduction are few. This is due, in part, to the requirement that new cancer-preventive drugs must first be shown to be efficacious in reducing cancer incidence or mortality. Moreover, such drugs need to have proven safety for long-term administration. This process can be improved by focusing on precancer (intraepithelial neoplasia) to identify subjects at risk and prove efficacy in shorter, smaller trials as well as on detecting early markers of potential toxicities of chronic exposure to cancer-preventive drug regimens.

摘要翻译： 

尽管研究界和公众都高度关注，但获批用于癌症预防和/或降低癌症风险的药物仍寥寥无几。部分原因在于，新的癌症预防药物必须首先证明能有效降低癌症发病率或死亡率；此外，这类药物还需证明适合长期使用的安全性。若能聚焦于癌前病变（上皮内瘤变）来筛选高风险人群，并在更短、更小规模的试验中验证疗效，同时及早发现长期用药可能带来的毒性标志，这一进程将有望加快。

原文链接：

Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development