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Comparison of the Oncogenicities of Four Structurally Isomeric N-Hydroxyxanthines¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The oncogenicities of all of the four possible isomeric N-hydroxyxanthines have been compared. For the two that were active, the proportions of tumors induced at the s.c. site of administration and their types were dose dependent. 3-Hydroxyxanthine, the isomer derived from N-oxidized guanine, induced sarcomas in 88 to 100% of the rats given 24 doses of 1 mg; at 0.1 mg both sarcomas and fibromas appeared in 25 to 58% of the rats. Total doses of 3-hydroxyxanthine ranging from 12 to 66 mg/rat induced s.c. tumors in 25 to 90% of the rats, some of which had hepatocellular carcinomas also.

The oncogenicity of the 7-hydroxyxanthine approaches that of the 3-isomer, particularly in the induction of liver tumors. In equal doses given s.c., 7-hydroxyxanthine induced both s.c. and liver tumors in 40% of the rats, compared with 89% for 3-hydroxyxanthine. Liver tumors were induced in 45 and 65% of the rats given i.p. injections in equal doses of 7- and 3-hydroxyxanthine, respectively, a nonsignificant difference. Several similarities between the chemical properties of 7-hydroxyxanthine and those of the 3-isomer correlated with their oncogenicities.

The 9-hydroxyxanthine showed no oncogenicity, explicable because of the stability of its sulfate ester. The 1-isomer was not oncogenic in this assay although it has induced some tumors at larger doses, but there is no explanation of its oncogenicity through any correlation of its chemical properties with those of the 3- and 7-isomers.

¹ This investigation was supported in part by USPHS Research Grants CA 15274, CA 17085, and CA 08748 from the National Cancer Institute. This is Paper 68 of a series titled "Purine N-Oxides." An abstract was presented at the 68th Annual Meeting of the American Association for Cancer Research, Denver, Colo., May 18 to 21, 1977 (6).

² To whom requests for reprints should be addressed, at Donald S. Walker Laboratory, Sloan-Kettering Institute for Cancer Research, 145 Boston Post Road, Rye, N. Y. 10580.

³ Present address: Department of Pathology, Lawrence Hospital, Bronxville, N. Y.

⁴ David A. Gimbel Memorial Fellow, 1970 to 1971. Present address: Hebrew University, Jerusalem, Israel.

Received 1/23/78. Accepted 4/12/78.