Development of carcinogenicity testing system using human skin xenografts transplanted to SCID mice and testing system for cancer chemopreventive agents

将异种人体组织移植到免疫缺陷小鼠身上似乎是提供与人类癌症发生有关的有用信息的最有希望的方法。在这项研究中，我们试图利用已知的致癌物对移植到免疫缺陷的CB-17 SCID(SCID)小鼠的人皮肤进行化学致癌。将致癌物7，12-二甲基苯并[a]菲(DMBA)、苯并[a]芘、甲基胆蒽、N-甲基-N‘-硝基-N-亚硝基-N-亚硝胺局部应用于人皮肤移植物，每周一次，持续25-30周(因为小鼠在实验开始后约25-30周死于致癌物毒性)，但未能产生皮肤肿瘤。DMBA加UV-B照射和上述四种药物单独加UV-B照射均不能产生肿瘤。以DMBA为引发剂和TPA为促进剂的人皮肤异种…两阶段致癌实验更多的FTS也未能发展为肿瘤。这些治疗均可诱导宿主CD-1小鼠皮肤出现乳头状瘤。DMBA诱导同种异体CD-1小鼠皮肤移植到SCID小鼠的皮肤乳头状瘤。用胶带部分去除人皮肤移植物的角蛋白层完全没有诱导肿瘤的作用。我们还尝试将绒猴(非人灵长类)皮肤移植到SCID小鼠身上，最终成功地将绒猴皮肤移植到SCID小鼠身上。利用这些绒猴皮肤异种移植，进行了DMBA的致癌性试验。同样，在移植的绒猴皮肤中没有出现肿瘤。当DMBA直接作用于CD-1小鼠和猴的背部皮肤时，分别在9周内诱发CD-1小鼠皮肤乳头状瘤，在35周内诱发绒猴皮肤乳头状瘤，表明人和猴皮肤对这些致癌刺激的敏感性远低于小鼠皮肤。由于致癌物毒性，人皮肤移植到SCID小鼠身上的寿命较短，也可能阻碍测试系统的发展。较少

Use of xenotransplanted human tissues to immunodeficient mice seems to be the most promising way to provide useful information relating to human carcinogenesis. In this study, we attemptted to conduct chemical carcinogenesis on human skin xenografts transplanted to immunodeficient CB-17 scid (SCID) mice using well known carcinogens which induce skin papillomas and carcinomas. Topical application of a carcinogen, i.e.7,12-dimethylbenz [a] anthracene (DMBA), benzo [a] pyrene, methylcholanthrene, N-methyl-N'-nitro-N-nitrosoguanidine, to the human skin xenografts once a week for 25-30 weeks (since mice died of toxicity from carcinogen at around 25-30 weeks after the start of experiments) failed to produce skin tumors. Both DMBA application plus UV-B irradiation and slternate applications of the above four agents in combination with UV-B irradiation also failed to produce tumors. Two-stage skin carcinogenesis experiments, i.e.DMBA as an initiator and TPA as a promoter, in human skin xenogra … More fts also failed to develop tumors. All of these treatments induced skin papillomas in skins of host CD-1 mouse. DMBA induced skin papillomas in allogenic CD-1 mouse skin grafts transplanted to SCID mice. Partial removal of keratin layr of human skin xenografts by tape was totally ineffective for tumor induction. We also tried to transplant marmoset (non-human primate) skin to SCID mice, and finally marmoset skin was successfully transplanted to SCID mice. Using these marmoset skin xenografts, a carcinogenicity test of DMBA was conducted. Again, no tumor was developed in transplanted marmoset skin. When DMBA was directly applied either to dorsal skins of CD-1 mice or marmosets, DMBA induced skin papillomas within 9 weeks in CD-1 mice and 35 weeks in marmosets, respectively.These results indicate that susceptibility of human and marmoset skin to these carcinogenic stimuli is much lower than that of mouse skin. Short life span of human skin transplanted to SCID mice due to carcinogen toxicity may also hinder the development of the testing system. Less