H. Gutmann, S. B. Galitski, W. A. Foley
Aug 1, 1967
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Influential Citations
30
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Quality indicators
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Cancer research
Abstract
Summary Two essentially noncarcinogenic aromatic amides, N -2-fluorenylbenzamide and N -(7-hydroxy-2-fluorenyl)acetamide, were converted, by synthetic N -hydroxylation, to the highly carcinogenic arylhydroxamic acids, N -hydroxy-2-fluorenylbenzamide and N -hydroxy-(7-hydroxy-2-fluorenyl)acetamide, respectively. N -Hydroxy-2-fluorenylbenzamide when administered intraperitoneally gave a 100% tumor incidence in those young female rats which were alive 8 weeks after the administration of the compound. The tumor incidence in male rats was 75%. The majority of the tumors (8/11) in female rats and all of the tumors (6/6) in male rats were rapidly growing and highly invasive intraperitoneal sarcomas. In addition, female rats developed mammary adenocarcinomas. N -Benzoylphenylhydroxylamine, an analog of N -hydroxy-2-fluorenylbenzamide in which the fluorenyl moiety was replaced by the phenyl group, was not carcinogenic. These results suggest that metabolic N -hydroxylation may be a necessary, but not sufficient, condition for carcinogenesis by aromatic amides. Metabolic studies carried out in the female rat with the use of N -hydroxy-2-fluorenylbenzamide and of N -2-fluorenylbenzamide labeled with 14 C in the α-carbon atom of the benzoyl group indicated that the benzoyl group of N -hydroxy-2-fluorenylbenzamide-α- 14 C was cleaved in vivo from the arylhydroxamic acid, as shown by the isolation of N -benzoyl-α- 14 C-glycine and of benzoic-α- 14 C acid from the urine. The data imply that N -2-fluorenyl-hydroxylamine, potentially a proximate agent in carcinogenesis by N -2-fluorenylacetamide and N -hydroxy-2-fluorenylacetamide, is a product of the metabolism of N -hydroxy-2-fluorenylbenzamide. Examination of rat urine or bile after the intraperitoneal administration of N -2-fluorenylbenzamide-α- 14 C disclosed only negligible amounts of N -hydroxy-2-fluorenylbenzamide. These experiments favor the view that the lack of carcinogenicity of certain aromatic amides for the rat may be explained by the inability of this species to N -hydroxylate the amide to the corresponding hydroxamic acid at a significant rate.