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Purine N-Oxides

XIX. On the Oncogenic N-Oxide Derivatives of Guanine and Xanthine and a Nononcogenic Isomer of Xanthine N-Oxide^{1, 2,}

Division of Experimental Chemotherapy and the Division of Biological Chemistry, Sloan-Kettering Institute for Cancer Research; Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University Medical College, New York, New York 10021

The oncogenic N-oxide derivatives of xanthine and guanine are now considered to be primarily the 7-hydroxyxanthine and 7-hydroxyguanine tautomers of the N-oxides. Additional assays of this xanthine derivative at 3, 5, or 7 mg/rat/week have continued to lead to nearly 100% incidence of a variety of tumors at the site of the subcutaneous injection. At a 3-mg dose level the guanine derivative also led to a 100% incidence of tumors at the site, and the two must now be considered equally oncogenic.

An isomeric xanthine N-oxide, 3-hydroxyxanthine, has proven inactive, which indicates that considerable structural specificity is required for oncogenicity.

At a very high dose level, 6-mercaptopurine 3-N-oxide induced tumors at the site of injection in 3 of 15 rats.

The parent purines, xanthine and guanine, as well as adenine, have not induced tumors at the site of injection, but, in a small series of rats, the incidence of tumors elsewhere was slightly higher than the presently known incidence of spontaneous tumors in other controls.

¹ This work has been supported in part by funds from the National Cancer Institute, NIH, USPHS (CA-08748), and the Atomic Energy Commission (Contract No. AT[30-1]-910).

² Part of this work was presented at the 57th Annual Meeting of the American Association for Cancer Research, Denver, Colorado, May 1966 and the 9th International Cancer Congress, Tokyo, Japan, October, 1966.

Received 9/21/66. Accepted 12/29/66.