This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Andersen, R. A. Articles by Miller, J. A. Search for Related Content PubMed PubMed Citation Articles by Andersen, R. A. Articles by Miller, J. A.

Carcinogenesis and Inhibition of the Walker 256 Tumor in the Rat by trans-4-Acetylaminostilbene, Its N-Hydroxy Metabolite, and Related Compounds^*

Roger A. Andersen, Makoto Enomoto, Elizabeth C. Miller and James A. Miller

( McArdle Memorial Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison, Wisconsin)

N-Hydroxy-4-acetylaminostilbene (N-hydroxy-AAS) was identified as a urinary metabolite of 4-acetylaminostilbene (AAS) and 4-aminostilbene (AS) in the rat. This metabolite was isolated and characterized in crystalline form. 3-Hydroxy-4-acetylaminostilbene (3-hydroxy-AAS) and AAS were also identified as urinary metabolites of AAS, AS, and N-hydroxy-AAS. In tests in male and female rats by intraperitoneal, subcutaneous, and oral routes N-hydroxy-AAS was a stronger carcinogen than AAS or AS in the mammary glands, forestomach, subcutaneous tissue, and small intestine of the rat. The three compounds appeared to be equally carcinogenic in the ear duct glands. In no case was N-hydroxy-AAS less active than AAS or AS. The data suggest that N-hydroxy-4-acetylaminostilbene is one of the proximate carcinogenic metabolites in carcinogenesis by 4-acetylaminostilbene.

N-Hydroxy-4-acetylaminobibenzyl, albeit a weak carcinogen, had greater carcinogenic activity than 4-acetylaminobibenzyl toward the mammary gland of the rat.

N-Hydroxy-AAS exhibited considerably greater inhibitory action than did AAS or AS on the growth of the Walker 256 tumor in the rat; the o-hydroxy metabolite, 3-hydroxy-AAS, had no effect on this tumor. The N-hydroxy metabolite is probably responsible for a major portion of the inhibition of this tumor in the rat by derivatives of AS.

Syntheses and properties are presented for the following new compounds: N-hydroxy-AAS and N-acetoxy-AAS; N-hydroxy-AS; 3-hydroxy-AAS; the 4'-fluoro derivatives of 4-nitrostilbene, AS, AAS, N-hydroxy-AAS, and N-acetoxy-AAS; 4-acetylaminobibenzyl and its N-hydroxy derivative; and the cupric chelate of N-hydroxy-AAS.

^* This investigation was supported by a research training grant, CRTY-5002, and by Grant C355 of the National Cancer Institute, United States Public Health Service; by a grant from the Jane Coffin Childs Memorial Fund for Medical Research; and by the Alexander and Margaret Stewart Trust Fund. We wish to thank Mrs. Joan Craig, Mrs. Nancy Kehm, Mrs. Judy Kissinger, and Mrs. Wai Won Moy for valuable assistance.

A preliminary report of these studies was presented at a meeting of the American Association for Cancer Research at Toronto, Canada on May 23, 1963. Some of the data have been published in abstract form (3) and are part of a thesis submitted in partial fulfillment of the requirements for the Ph.D. degree by R. A. Andersen, University of Wisconsin, 1963. During the course of these investigations we learned from Dr. R. W. Baldwin, University of Nottingham, England, that he and his associates (4, 5, 48), were conducting similar experiments. We are grateful to Dr. Baldwin for this opportunity to exchange information.

Now at the Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York.

On leave from the Department of Pathology, University of Tokyo.

Received 9/ 6/63.