van Steeg H, Klein H, Beems R B, van Kreijl C F
Laboratory of Health Effects Research, National Institute of Public Health and the Environment, Bilthoven, The Netherlands.
Toxicol Pathol. 1998 Nov-Dec;26(6):742-9. doi: 10.1177/019262339802600605.
At present (putative) human carcinogens are identified via epidemiological studies and testing using the chronic 2-yr rodent bioassay. Both methods have severe limitations in that they are slow, insensitive, expensive, and are also hampered by many uncertainties. The development of methods to modify specific genes in the mammalian genome has provided promising new tools for use in identifying carcinogens and characterizing their (qualitative) risk. Several transgenic mouse lines are currently under study to test their possible use in short-term carcinogenicity testing. One such candidate alternative transgenic model is the XPA knock-out mouse. These mice have an almost complete deficiency in DNA nucleotide excision repair (NER). Nevertheless, XPA-deficient mice are viable and have a background of a low incidence of spontaneous development of cancers. Approximately 15% of the mice develop hepatocellular adenomas (only after 1.5 yr). After treatment with ultraviolet-B radiation or 7,12-dimethylbenz(a)anthracene, the XPA-deficient mice developed squamous cell carcinomas and papillomas, respectively, on their skin. Oral treatment of XPA-deficient mice with benzo[a]pyrene (B[a]P), 2-acetylaminofluorene (2-AAF), and 2-amino-1-methyl-6-phenylimidazo [4,5-b]-pyridine (PhIP) resulted in lymphomas (B[a]P), liver and bladder tumors (2-AAF), and intestinal adenomas plus lymphomas (PhIP). These results look encouraging, but it should be noted that the compounds and agents tested thus far have all been substrate for nucleotide excision repair. Animal studies with different genotoxic or nongenotoxic compounds, as organized for instance within the framework of the International Life Sciences Institute/Health and Environmental Sciences Institute program, are needed to further evaluate the suitability of the XPA model for short-term carcinogenicity testing.
目前，（假定的）人类致癌物是通过流行病学研究以及使用为期两年的慢性啮齿动物生物测定法进行检测来确定的。这两种方法都有严重的局限性，即它们速度慢、灵敏度低、成本高，而且还受到许多不确定性的困扰。在哺乳动物基因组中修饰特定基因的方法的发展为识别致癌物及其（定性）风险特征提供了有前景的新工具。目前正在研究几种转基因小鼠品系，以测试它们在短期致癌性测试中的可能用途。一种这样的候选替代转基因模型是XPA基因敲除小鼠。这些小鼠在DNA核苷酸切除修复（NER）方面几乎完全缺失。然而，XPA缺陷小鼠是有活力的，并且自发发生癌症的背景发生率较低。大约15%的小鼠会发生肝细胞腺瘤（仅在1.5年后）。在用紫外线B辐射或7,12-二甲基苯并(a)蒽处理后，XPA缺陷小鼠在其皮肤上分别发生了鳞状细胞癌和乳头状瘤。用苯并[a]芘（B[a]P）、2-乙酰氨基芴（2-AAF）和2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）对XPA缺陷小鼠进行口服处理，分别导致淋巴瘤（B[a]P）、肝脏和膀胱肿瘤（2-AAF）以及肠道腺瘤加淋巴瘤（PhIP）。这些结果看起来令人鼓舞，但应该注意的是，迄今为止测试的化合物和试剂都是核苷酸切除修复的底物。需要对不同的遗传毒性或非遗传毒性化合物进行动物研究，例如在国际生命科学研究所/健康与环境科学研究所项目框架内组织的研究，以进一步评估XPA模型在短期致癌性测试中的适用性。
