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The Metabolism of 4-Aminopyrazolo (3,4-d)pyrimidine in Normal and Neoplastic Tissues^*

J. Frank Henderson and Irene G. Junga

( Department of Biological Sciences, Stanford Research Institute, Menlo Park, California)

The metabolism of 4-aminopyrazolo(3,4-d)pyrimidine (APP)¹ has been studied in several normal and neoplastic mouse tissues.

APP is rapidly cleared from the peritoneal fluid and blood after intraperitoneal or intravenous administration. The drug is taken up by the blood cells and is lost from them less rapidly than from serum.

Approximately one-half of the administered drug is excreted in the urine from normal mice in 24 hours, and one-half of this is within the 1st hour. The rate and amount of excretion from tumor-bearing mice are much less.

The distribution of APP in the tissues was studied. Only in the tumor cells, small intestine, liver, and spleen did APP concentration increase during the first hour after administration.

The following were tentatively identified as metabolites of APP in the tissues: free APP, APP-riboside, 4-hydroxypyrazolo(3,4-d)pyrimidine, the mono-, di-, and triphosphates of APP-riboside, and two unidentified degradation products.

Liver, spleen, kidney, small intestine, muscle, and blood were quantitatively examined for their content of these metabolites over a 2-hour period following administration of APP. In all cases the total nucleotide fraction was quantitatively most important. The free base and degradation products were also present and were especially evident in blood and muscle.

In three sensitive and four resistant tumors the predominant metabolites were the nucleotides, at all three levels of phosphorylation. In addition, small amounts of the free base and degradation products were also present.

The metabolism of APP in the sensitive tumors was characterized either by the formation of relatively very large quantities of nucleotides or by continued nucleotide formation throughout the time period studied. Resistant tumors characteristically formed relatively smaller amounts of nucleotides or degraded those initially synthesized more rapidly than did the sensitive tumors.

All tissues and tumors studied incorporated APP into their nucleic acids. No correlation was found between the rate or extent of incorporation and sensitivity to this drug. In Ehrlich ascites carcinoma there was 10 times more incorporation into the ribonucleic acid (RNA) than into deoxyribonucleic acid (DNA). APP was shown to be incorporated into this RNA in nucleotide form.

The significance of these studies of APP metabolism is discussed.

^* This work was supported by Contract No. SA-43-ph-3068 with the Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, and by grants from the U.S. Public Health Service (CY-4551) and the Gustavus and Louise Pfeiffer Research Foundation.

¹ Abbreviations used: PCA, perchloric acid; RNA, ribonucleic acid; DNA, deoxyribonucleic acid; Ehrlich-TG-R, a thioguanine-resistant subline of the Ehrlich ascites carcinoma; APP, 4-aminopyrazolo(3,4-d)pyrimidine; XPP, degradation products of APP; APP-MP, APP-DP, APP-TP, the mono-, di-, and triphosphates of AP-riboside, respectively.

Present address: Department of Pharmacology, George Washington University School of Medicine, Washington, D.C.

Received 9/14/60.