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The Carcinogenicity of Compounds Related to 2-Acetylaminofluorene

II. Variations in the Bridges and the 2-Substituent^{* ,}

( McArdle Memorial Laboratory, Medical School, University of Wisconsin, Madison 6, Wis., and Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada)

1. The carcinogenic activities of fourteen compounds structurally related to 2-acetylaminofluorene and which differ principally in the nature of the bridges between the two aromatic rings have been determined in the rat. These compounds are the 2-acetylamino derivatives of 9-fluorenol, 9-fluorenone, phenanthrene, 9,10-dihydrophenanthrene, carbazole, pyrene, and dibenzothiophene; the 3-acetylamino derivatives of phenanthrene, carbazole, dibenzothiophene sulfone, and diphenylmethane; the 4-acetylamino derivatives of diphenylsulfide and biphenyl; and 1-acetylaminopyrene.

2. 2-Acetylaminofluorene induced high incidences of liver tumors in the males and of mammary gland tumors in the females and moderate incidences of tumors of the ear duct and small intestinal epithelium in both sexes.

3. A fluorene nucleus appears to be required for strong carcinogenic activity toward the liver. 2-Acetylamino-9-fluorenol and 2-acetylamino-9-fluorenone had weak activity; the other compounds were inactive.

4. A biphenyl nucleus is apparently necessary for carcinogenic activity toward the mammary gland. 4-Acetylaminobiphenyl was as active as 2-acetylaminofluorene, and a number of compounds with bridges in the 2, 2'-positions were also active.

5. The requirements for carcinogenicity toward the ear duct and intestinal epithelium were intermediate between those of the liver and mammary gland; in general, a tricyclic derivative was necessary.

6. 2-Acetylaminophenanthrene, in addition to inducing tumors of the mammary gland, ear duct, and intestinal epithelium, also had a moderate leukemogenic activity. When fed at higher levels, it induced a paralysis of the hind limbs.

7. 7-Fluoro-2-acetylaminofluorene was much more active toward the liver of both male and female rats than 2-acetylaminofluorene. The activity toward the other tissues was not enhanced by this fluoro-substitution.

8. In agreement with the work of others 2-nitro-, 2-amino-, and 2-dimethylaminofluorene were less active than 2-acetylaminofluorene at the usual sites. In addition, 2-nitrofluorene induced a high incidence of squamous-cell carcinomas of the forestomach.

9. On histological examination a high proportion of the tumors induced by each compound and at all sites were found to be malignant.

10. The syntheses of the following new compounds are described: 2-acetylaminocarbazole and 7-fluoro-2-acetylaminofluorene.

^* This work was supported by grants-in-aid from the National Cancer Institute, United States Public Health Service (No. C355), from the American Cancer Society upon recommendation of the Committee on Growth of the National Research Council, and from the Alberta Branch of the Canadian Cancer Society and by institutional grants from the American Cancer Society (INSTR 71B) and the Alexander and Margaret Stewart Trust Fund.

Paper 1 of this series is reference (39).

Received 12/ 1/54.