Mammary Carcinogenesis in the Rat by Topical Application of Fluorenylhydroxamic Acids1

One topical application of 0.02 mmole of /V-hydroxy-2fluorenylacetamide to the left thoracic glands of adult female Sprague-Dawley rats gave a 70% tumor incidence at the site. The tumors appeared 3 to 6 months after the application and were mammary adenocarcinomas. In contrast, the tumor incidence after application of N-2fluorenylacetamide was 30%, the latent period was 8 to 11 months, and the tumors were not confined to the site of application. /V-Hydroxy-3-fluorenylacetamide, a strong mammary carcinogen by the i.p. route, and /V-3-fluorenylacetamide, a marginally active mammary carcinogen, when applied locally showed a similar pattern of carcinogenicity as the 2-isomers. These data suggested that the fluorenylhydroxamic acids, rather than the arylamides, induce mammary tumors. Experiments comparing the microsomal /V-hydroxylation of /V-2and /V-3-fluorenylacetamide by mammary gland and liver showed that mammary gland microsomes, in contrast to those of liver, did not /V-hydroxylate the arylamides. Experiments con cerned with the sulfation of /V-hydroxy-2and -3-fluorenylacetamide by mammary gland gave no evidence that mammary gland formed the /V-sulfates of /V-hydroxy-2fluorenylacetamide or of /V-hydroxy-3-fluorenylacetamide. The data suggest that /V-hydroxylation may be implicated in mammary carcinogenesis. However, the two-step ac tivation mechanism believed to initiate hepatocarcinogenesis by /V-2-fluorenylacetamide does not appear to be operative in mammary gland.