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

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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