Van Deun K, Van Cauteren H, Vandenberghe J, Canning M, Vanparys P, Coussement W
Department of Toxicology, Janssen Research Foundation, Beerse, Belgium.
Adverse Drug React Toxicol Rev. 1997 Nov;16(4):215-33.
Hundreds of pharmaceuticals have been reported to give a positive result in the standard "Chronic Bioassay", which consists of an 18 to 24 month daily administration of the test compound in mice and rats. This is in contrast with 20 pharmaceuticals, which are known to be carcinogenic to humans. The high incidence of apparently false-positive results in the Chronic Bioassay may be related to differences in mechanism of pharmacological action between rodents and humans, but also to the very high dose levels that have to be administered to rodents in accordance to regulatory guidelines. Lack of relevance to man therefore often has to be demonstrated by additional mechanistic studies. Based upon the deficiencies of the Chronic Bioassay and on the increased knowledge on cellular and molecular mechanisms involved in carcinogenicity, extensive discussions have recently taken place between regulatory agencies and industry associations at the occasion of International Conferences on Harmonization (ICH). These discussions have resulted in the possibility to use alternative short-to-medium-term carcinogenicity models in combination with a single two-year carcinogenicity study for evaluation of carcinogenicity. A description of these models is provided in this review as well as possible strategies for carcinogenicity testing and evaluation in the future.
据报道，数百种药物在标准的“慢性生物测定”中呈现阳性结果，该测定包括在小鼠和大鼠中每日给予受试化合物，持续18至24个月。这与20种已知对人类具有致癌性的药物形成对比。慢性生物测定中明显假阳性结果的高发生率可能与啮齿动物和人类在药理作用机制上的差异有关，但也与根据监管指南必须给予啮齿动物的非常高的剂量水平有关。因此，通常必须通过额外的机制研究来证明其与人类的相关性不足。基于慢性生物测定的缺陷以及对致癌作用所涉及的细胞和分子机制的认识增加，监管机构和行业协会最近在国际协调会议（ICH）期间进行了广泛讨论。这些讨论使得有可能使用替代的短期至中期致癌性模型，并结合一项为期两年的致癌性研究来评估致癌性。本综述提供了这些模型的描述以及未来致癌性测试和评估的可能策略。
